SK142099A3 - 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds - Google Patents

Abstract

A compound having formula (I), wherein R<1>, R<2>, R<3> and R<4> are defined variables selected from the groups as specified herein which include alkyl, aryl, heteroaryl and heterocyclic and substituted versions thereof, 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, nociperception, pain, 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 of preparation thereof.

Description

Compounds of 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine, preparation and method of inhibiting adenosine kinase

Technical field

The present invention relates to a method of inhibiting adenosine kinase by administering 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine compounds, pharmaceutical compositions containing these compounds as well as novel compounds of 6,7-disubstituted-4-aminopyrido [2,3-d] ] pyrimidine.

BACKGROUND OF THE INVENTION

Adenosine kinase (ATP: adenosine-5'-phosphotransferase, EC 2.7.1.20) is a ubiquitous enzyme that catalyzes phosphorylation of adenosine to AMP, using ATP preferentially as a phosphate source. Adenosine kinase has a tissue distribution and species distribution and has been isolated from yeast, various mammalian sources and certain microorganisms. It has been found to be virtually present in any human tissue analyzed, including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in the regulation of cellular concentrations of adenosine.

Adenosine is a purine nucleoside that is an intermediate in purine nucleotide degradation and replacement cycles. Adenosine also has many important physiological effects, many of which are mediated through the activation of specific ectocellular receptors, expertly designated Pi receptors (Burnstock, Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds.) Raven, New York) , 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., Cerebrovasc. Brain Metab. Rev. 1992, 4: 346-360), acts as an endogenous anticonvulsant (Dragunow,

Trends Pharmacol. Sci. 1986, 7 '128-130) and may play a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine may play a role in various central nervous system disorders such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, M., in Psychopharmacology: The Fonrth Generation of Progress, Bloom, Kupfer (eds.), Raven Press, New York, 1995, 643-655).

Adenosine has also been implicated in modulating transmission in spinal cord pain pathways (Sawynok, et al., Pharm. / Pharmacol., 1986, 88; 923-930) and in mediating the analgesic effects of morphine (Sweeney, et al., J. Phramacol. Exp. Ther. 1987, 243: 657-665).

In the immune system, adenosine inhibits certain neutrophil functions and exerts anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). An AK inhibitor has been found to reduce paw swelling in a model of arthritis adjuvant in rats (Firestein, et al., Arthritis and Rheumatism, 1993, 36, S48).

Adenosine also exhibits various effects on the cardiovascular system including vasodilation, atrioventricular conduction damage, and endogenous cardiac protection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, 289-4) ). The extended action of adenosine also includes effects on the renal, respiratory, gastrointestinal and reproductive systems as well as on blood cells and adipocytes. By inhibiting lipolysis, adenosine plays a role in diabetes by activating its A 1 receptor on adypocytes (Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551)

It appears that the released endogenous adenosine plays a role as a natural defense mechanism in various pathophysiological conditions including cerebral and myocardial ischemia, seizures, pain, inflammation and infection. While adenosine is commonly present at low levels in the extracellular space, its release is locally elevated at the site (s) of excess cellular activity, trauma or metabolic stress.

Adenosine in the extracellular space activates specific extracellular receptors. to induce various responses that lead to normalization of cellular functions. (Bruns, Nucleosides Nucleolides, 991, 10: 93 1-943; Miller and Hsu, J. Neurotrciuma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., J. Physiul. 1989, 25: C799-C806) and its endogenous effects are therefore highly localized.

Inhibition of adenosine kinase may result in an increase in local concentrations of adenosine in the focus of the injured tissue, further increasing cell protection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby reducing systemic toxicity to the lowest level.

Pharmacological compounds causing adenosine kinase inhibition provide potentially effective new therapies for disorders promoted by local and specific potentiation of adenosine. Disorders where these compounds may be useful include conditions of ischemia such as cerebral ischemia, myocardial ischemia, angina, coronary artery graft bypass surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other thrombotic and embolic disorders and neurological conditions such as epilepsy, anxiety, schizophrenia, nociperception including painful perception, neuropathic pain, visceral pain as well as inflammation, arthritis, immunosuppression, infection, diabetes and gastrointestinal dysfunction as well as abnormal gastrointestinal motility.

A number of compounds that inhibit adenosine kinase have been disclosed. The most effective of these are 5'-amino-5'-deoxyadenosine (Miller, et al., Riol. Chem. 1979, 254: 2339-2345), 5-iodotubercidine (Wotring and Townsend, Caucer lies 1979). , 39: 3018-3023) and 5'-deoxy-5-iodotobercidin (Davies, et al., Riochem. Harmacol. 1984, 33: 347-355).

Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Fiol. Chem. 1979, 254: 2339-2345) including tubercidine, formycin, ribavirin, pyrazofurine and 6- (methylmercapto) purinriboside. These purine nucleoside analogs represent an important class of antimetabolites possessing cytotoxic, antitumor, and antiviral properties. They are administered as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form. Loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogues (e.g., Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al., Can. J. Biochem., 1967 , 45: 735-744; Suttle, et al., European J. ('ancer, 1981, 17: 43-51). Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2 deoxyadenosine (Hershfield and Kredich, Prac. Natl Acad Sci (ISA, 1980, 77: 4292-4296) The accumulation of deoxyadenosine triphosphate (dATP), derived from 2'-deoxyadenosine phosphorylation, has been proposed as a toxic mechanism in the immune deficiency associated with hereditary adenosine deaminase deficiency. , in The Metaholic Baxis of Inherited Diseases, 1989 (Scriver, et al., eds.), McGraw-Hill, New York, 1045-1075.

B.S. Hurlbert et al. (J. Med. Chem., II: 71 1-717 (1968)) disclose various 2,4-diaminopyrido [2,3-d] pyrimidine compounds which are used as antibacterial agents. R. K. Robins et al. (J. Amer. Chem. Soc., 80, 3449-3457 (1958)) disclose processes for the preparation of many 2,4-dihydroxy-, 2,4-diamino, 2-amino-4-hydroxy- and 2-mercapto-4-hydroxypyrido [2,3-d] pyrimidines having activity against the folic acid R. Sharma et al. (Ind., Chem., 31B: 719-720 (1992)) disclose 4-amino-5- (4-chlorophenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pyrimidine and 4-amino compounds. no-5- (4-methoxyphenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pyrimidine having antibacterial activity. A Gupta et al., J. Indian Chem. Soc., 71, 635-636 (1994)) disclose compounds 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)) disclose compounds

4-amino-5-phenyl-7- (4-aminophenyl) pyrido [2,3-d] pyrimidine, 4-amino-5-phenyl 1-7 (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., Telrahedron, 51: 10253-10258 (1995)) disclose the synthesis of 45 amino-5,7-diphenylpyrido [2,3-d] pyrimidine compounds from acyclic precursors. Bridges et al. (PCT Patent Application No. WO 95/19774 published on July 27, 1995) discloses various bicyclic heteroaromatic compounds that are useful for inhibiting epidermal growth factor tyrosine kinase.

SUMMARY OF THE INVENTION

The present invention provides compounds of 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine useful as adenosine kinase inhibitors. In this aspect, the present invention provides novel compounds having the general formula (I)

(O wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to three additional heteroatoms selected from the group consisting of O, N, or S;

R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, and the dotted line indicates an optional double bond.

The present invention also relates to pharmaceutically acceptable salts and amides of the compounds of formula (I) and their use is discussed below.

In another aspect, the present invention provides a method for inhibiting adenosine kinase by administration of a compound of formula (I).

In particular, the method of inhibiting adenosine kinase comprises exposing adenosine kinase to an effective inhibitory amount of a compound of formula (1) of the present invention. When the adenosine kinase is localized in vivo, the compound is administered to the body.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound of formula (1) in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of treating ischemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal dysfunction, diabetes and infection in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (1) of the invention.

I ’’ '

In a preferred aspect, the present invention provides a method of treating cerebral ischemia, myocardial ischemia, angina, coronary artery graft bypass surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, thrombotic and embolic states, perilepsy, anxiety, anxiety, anxiety, anxiety, anxiety , neuropathic pain, visceral pain, arthritis, infection, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (1) of the present invention.

The present invention also relates to pharmaceutically acceptable salts and amides of the compounds having formula (1) of their use for inhibiting adenosine kinase in pharmaceutical compositions and for administration to mammals.

In addition, the present invention relates to a compound of formula (II)

wherein R 1 and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom;

R ³ and R ⁴ are independently selected from lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic.

In a further aspect, the present invention also provides a process for the preparation of compounds of formula (II)

(Π) wherein R ¹ and R ² are hydrogen, R 1 is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic, R ⁴ is aryl, heteioaryl or heterocyclic; the process comprising (a) reacting 4,6-diamino-5-iodopyridinidine with an ethenylboronic acid derivative having the general formula (HO) ₂ B ₃ wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or a substituted version thereof, in the presence of tetrakistriphenylphosphine palladium and an aqueous alkali metal base, and isolation of the first intermediate of formula

R ³ (b) reacting the first intermediate with an aldehyde of a compound having the formula R ⁴ CHO, wherein R ⁴ is an aryl, heteroaryl or heterocyclic group, under anhydrous conditions and with the removal of water from the reaction, and isolating the compound of formula (II).

In another aspect, the present invention provides a process for the preparation of compounds of formula (II)

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom in which both R ¹ and R ² cannot be hydrogen, R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic;

R ⁴ is aryl, heteroaryl or heterocyclic; the method comprising (a) reacting a compound having the general formula (II)

(II) wherein R ¹ and R ² are hydrogen;

substituent R ^? is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group;

R ⁴ is an aryl, heteroaryl or heterocyclic group; with a compound selected from the group consisting of (i) an alkylating agent of formula R * -Y, wherein R ¹ is lower alkyl and Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate;

(ii) an arylalkylating agent of formula R'-lower alkyl-Y, wherein R ¹ is arylalkyl and Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate;

(iii) an acyl compound of formula R 1 -Z, wherein R ¹ is acyl and Z is selected from the group consisting of an acid anhydride moiety, a halide, or an acyl activating group;

and (b) optionally, if desired that R ² should not be hydrogen, reacting the compound of step (a) with a compound selected from the group consisting of (i) an alkylating agent of formula R ² -Y, v; wherein R ² is lower alkyl and Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate;

(ii) alkylating agents R ² -Y-lower alkyl, wherein ^R2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate;

(iii) an acyl compound of formula R ² -Z, wherein R ² is acyl and Z is selected from the group consisting of an acid anhydride, a halide or an acyl activating moiety;

In another aspect, the present compounds of formula (I-1) also provide a method of preparation

wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom, with the proviso that both R ⁴ and R ⁵ are not hydrogen;

R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group;

R ⁴ is aryl, heteroaryl or heterocyclic; the method comprising (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the general formula (HO) _2Bx ^ ₃ wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl , a heterocyclic group or heteroaryl, in the presence of tetrakistriphenylphosphine palladium (O) and an aqueous base of alkali metals, and isolating the first intermediate having the general formula

R ³ (b) reacting the first intermediate with an aldehyde compound having the formula R ⁴ CHO, wherein R ⁴ is an aryl, heteroaryl or heterocyclic group, under anhydrous conditions and with removal of water from the reaction, and isolating the second

and (c) reacting the fourth intermediate with an amine compound having the general formula R 1 -NH-R ² , wherein R ¹ and R ² are as described above, and isolating the desired product.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine compounds useful in the inhibition of adenosine kinase, pharmaceutical compositions containing these compounds, a method of using the compounds to inhibit adenosine kinase, as well as novel compounds of 6,7-disubstituted 4-aminopyrido [2,3-d] pyrimidine.

In this aspect, the present invention provides 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine compounds that are adenosine kinase inhibitors. The adenosine kinase inhibitor of the present invention is the aforementioned compound of formula (I) or (TI).

In a preferred embodiment, the adenosine kinase inhibitor of the present invention is the aforementioned compound of formula (1) or (II) wherein R ⁴ is aryl or heteroaryl or a substituted version thereof

In a more preferred embodiment, the adenosine kinase inhibitor of the present invention is the aforementioned compound of formula (1) or (11) wherein R ⁴ is aryl or heteroaryl and substituted versions thereof and R 1 is lower alkyl, aryl, arylalkyl or heteroaryl or substituted versions

In another embodiment, the present invention relates to the aforementioned compounds of formulas (I) and (II) wherein R ¹ and R ² are independently selected from the group consisting of hydrogen, lower alkyl, arylC 1 -C 6 alkyl, -C (O) C 1 -C 6 alkyl, -C (O) aryl, -C (O) aryl, C (O) heterocyclic, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring, optionally containing one up to two additional heteroatoms selected from O, N, S;

R ⁴ and R ⁴ are independently selected from the group consisting of:

C Cealkylu,

C Cealkenylu.

C 2 Cealkynylu,

C3-cycloalkyl, R _p heteroaryl-C ₆ alkyl, or substituted heteroaryl-C ₆ alkyl, aryl-Co-Cealkylu or substituted aryl-Cealkylu, heteroarylC2-Cealkenylu or substituted heteroarylC2 6 alkenyl, arylC2-Cealkenylu or substituted arylC2-C6 alkenyl, heteroarylC2-Cealkynylu or substituted heteroaryl-C 2 -C 8 alkynyl, arylC 2 -C 8 alkynyl or substituted arylC 2 -C 8 alkynyl wherein the substituents

1-4 heteroaryl or aryl are independently selected from the group consisting of halo, oxo, cyanoC 1 -C ₆ alkyl, heteroarylC 0 -C ₆ alkyl, heterocyclic C ₀ -C ₆ alkyl, C 1 -C ₆ alkyloxyC 1 -C 6 alkyl, arylCoC 6 alkyl, arylC 1 -C ₆ alkyl, R 1 ^with R ^f, NC (O), cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyldialkyl-malonyl, CF 3, -OH, C 1 -C 6 alkyloxyC 1 -C 6 alkyloxy, C 1 -C 6 alkylSO 4, wherein n is 1-2, C 1 -C 6 alkylthio, C 1 -C 6 alkylacryl, CF 3 O, CF 3, C 1 -C ⁴ alkylenedioxy, C 1 -C 6 alkyl acrylic, R ⁵ R ⁶ N (CO) NR ⁵ , Nformyl (heterocyclic), NO 2, NR ^{6 with} R ⁶ C 0 -C 6 alkyl wherein R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, HC (O), C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylC (O), CF, C (O), NR ⁷ R ⁸ C -CňalkylC (O), ftalimidoC] -C6C (O), C CôalkylSO ,,, wherein n is 1-2, CNC | _Ï -C alkyl, R ⁷ R ⁸ NC (O) NR ⁷ - , heteroaryl, NR ⁷ R ⁸ C 1 -C ₆ alkylC (O). · C CôalkyloxykarbamidoCi-Cňalkyki, wherein R and R are independently selected from those variables are as defined for the substituents R ⁵ and R ^N or the substituents R ^5, and R ^fi, or the substituents R ⁷ and R ⁸ may combine together with the nitrogen to which they are attached to form a five to seven membered unsubstituted or substituted ring or optionally containing one to three additional heteroatoms selected from O, N or S, wherein the substituents are selected from C 1 -C 6 alkyl and wherein, in the case of formula (1) , the dashed line indicates a double bond, if any. The invention also includes the compounds having the substituents R 'and R ^J are independently selected from the groups listed below the 6-substituted and 7-substituted groups.

Exemplary and preferred compounds of the invention include:

4-amino-6-phenyl-7- (p-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (dimethylamino) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7-phenyl-pyrido [2,3-d] pyrimidine;

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

4-amino-6- (4- (dimethylamino) phenyl) -7- (4-pyridinyl) pyiido [2,3-d] pyrimidine;

4-amino-6- (4- (dimethylamino) phenyl) -7- (4-bromophenyl) pyľido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (4- (5-pyrimidinyl) feiiyl) -pyrido [2,3-d] pyrimidin;

4-amino-6- (4-methylphenyl) -7- (4- (2- (2-pyridinyl) ethenyl) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (3-pyridinyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (thiophen-3-yl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-metyIfenyI) -7- (2-pyridinyl) pyrido [Z, 3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (3,4-methylenedioxyphenyl) -pyrido [2,3-d] pyrimidine;

4-amino-6-butyl-7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6-butyl-7- (thiophen-3-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (5-bromo-thiophen-2-yl) pyľido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (5-methyl-thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (4- (tľifhiórmetoxy) phenyl) pyrido [2,3-d] pyrimidine,

4-amino-6- (4-methylphenyl) -7- (3-phenoxy-phenyl) -pyrido [2,3-d] pyrimidine;

4-amino-6-4-methyl-phenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (4-bromo-thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (3-methyl-thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (furan-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (furan-3-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (5-methyl-furan-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4- (2-propyl) phenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyr'imidín;

4-amino-6- (4- (2-propyl) phenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4- (dimethylamino) phenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (3,4-dimethoxyphenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine,

4-amino-6-hexyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyi'irnidin;

4-amino-6-hexyl-7- (thiophen-2-yl) pyľido [2,3-d] pyrimidine;

4-amino-6- (2-methyl-2-propyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (4- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine,

4-amino-6- (4-propylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidin,

4-amino-6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] -pyrimidin,

4-amino-6- (3-methoxyphenyl) -7- (4- (diinetylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (3-bi'ómfenyl) -7- (4- (dinietylamino) phenyl) pyrido [2,3-d] pyrimidine,

4-amino-6- (3-fluorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine,

4-Amino-6- (3-trifluoromethylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (3-chlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3,5-dichlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

, I

4-amino-6- (3,4-methylenedioxyphenyl) -7- (4- (dimethylamino) phenyl) p'yrido [2,3-d] pyrimidine;

4-amino-6- (3,4-methylenedioxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (3-methoxycarbonylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (3- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4- (2-methyl-2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-fluoro-phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3- (phenylmethoxy) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-chlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (3-fluoro-4-methylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (3-fluoro-4-methylphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-phenylpropyl) -7- (4-methoxyphenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (3-phenylpropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine, 4-amino-6- (2-phenylethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (phenylmethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (cyclolexylmethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6-butyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6-pentyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (2-methylpropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-Amino-6-propyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-cyano) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-Amino-6- (3-nitrophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6-pentyl-7- (thiophen-2-yl) -pyrido [2,3-pyrimidine;

4-amino-6- (3-carboxamidopropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6 - ((4-methoxyphenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6 - ((3-bromophenyl) methyl) -7- (tiofert-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6 - ((4- (2-propyl) phenyl) methyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine;

4-amino-6 - ((4-methoxyphenyl) methyl) -7- (4- (2-propyl) phenyl) pyrido [2,3-d] pyrimidine

4-amino-6 - ((4-bromophenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6 - ((3-fluorophenyl) methyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine;

4-amino-6 - ((4-bromophenyl) methyl) -7- (thiazol-2-yl) -pyrido [2,3-pyrimidine;

4-amino-6 - ((3-methoxyphenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-Amino-6- (phenylmethyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine;

4-amino-6 - ((3-methoxyphenyl) methyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (4- (trifluoromethyl) phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methylphenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methoxyphenyl) -pyrido [2,3-d] pyrimidine; 4-Amino-6- (4-methylphenyl) -7- (4-ethylphenyl) pyrido [2,3-d] pyrimidine, 4-amino-6- (4-methylphenyl) -7- (4-cyanophenyl) pyrido [ 2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-acetamidophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-phenoxyphenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-fluorophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-chloro-phenyl) -pyrido [2,3-djpyritrudín; 4-amino-6- (4-methylphenyl) -7- (4-aminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methylthiophenyl) pyrido [2,3-d] pyrimidine, 4-amino-6- (4-methylphenyl) -7 - ((4-phenyl)) phenyl) pyrido [2,3-d] pyrimidine, 4-amino-6- (4-methylphenyl) -7 - ((4-phenylmethoxy) phenyl) pyrido [2,3-d] pyrimidine, 4-amino-6 - (4-methylphenyl) -7 - ((4-N, N-diethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7 - ((4-2-phenylethenyl) phenyl) pyrido [2,3-d] pyrimidine, 4-amino-6- (4-methylphenyl) 7- (4- (2-methyl-2-propoxy) phenyl) pyrido [2,3-pyrimidine:

4-amino-6- (4-methylphenyl) -7- (3-chlorophenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (3,5-dimethoxyphenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (thiophen-2-yl) -7- (4-N, N-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine; 4-Amino-6- (4-methylphenyl) -7- (benzofuran-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (thiophen-2-yl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (thiophen-2-yl) -7- (4-methoxyphenyl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-Bromo-phenyl) -7- (4-N, N-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine;

4-amino-6- (3-bromo-4-methoxy-phenyl) -7- (4-N, N-dimetyIaminofenyI) -pyrido [2,3-d] pyrimidine;

4-amino-6- (3-bromo-4-methoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-butoxy-phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-methoxyphenyl) pyrido [2,3-d] pyrimidine; and 4-amino-6- (4-methylphenyl) -7- (3,5-dichlorophenyl) pyrido [2,3-d] pyrimidine.

The present invention also encompasses those reduced versions of the compounds described above in which the right side of the bicyclic ring can be reduced or partially reduced as shown in formula (I) by catalytic hydrogenation or other known reduction processes to produce the compounds as above, wherein: 5.6 and / or 7.8 the double bond is absent or where the double bond is between carbon atoms 6 and 7. It is contemplated that the final compounds shown above can be readily reduced and so are included within the scope of the invention.

Furthermore, the substituents R ³ and R ^J may independently be selected from phenyl; thiophen-2-yl; 1-methyl-2-oxobenzoxazolin-5-yl; 2- (dimethylamino) -5-pyrimidines 1; 2- (N-formyl-N-methylamino) -3-pyrimidinyl; 2- (N- (2-methoxyethyl) N-methylamino) -5-pyrimidinyl; 2- (N-methylamino) 5-pyrimidinyl; 2- (1-morpholinyl) -5-pyrimidinyl; 2- (1-pyrrolidinyl) -5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3- (dimethylamino) phenyl, 3 amino-4-methoxyphenyl; 3-bromo-4- (dimethylamino) phenyl; 3-Methoxyphenyl, 3-methyl-4- (N-acetyl-N-methylamino) phenyl; 3-methyl-4- (N-formyl-N-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; 3,418 methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4- (acetylamino) phenyl; 4 (dimethylamino) -3-fluorophenyl; 4- (dimethylamino) phenyl; 4- (imidazol-l-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) fertyl; 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-amino) -phenyl; 4- (Nmorfoli.nyl) 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-butoxy-phenyl; 4-karboxamidofenyI; 4-chlorophenyl; 4-cyanophenyl; 4-dietyIaminofenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropyl-phenyl; 4-methoxyphenyl); 4-metyIaminofenyl; 4-methylsulfonylphenyl; 4-morfolinyIfenyl; 4-N- (2- (dimethylamino) ethyl) -Nformylamino) phenyl; 4-N- (3-methoxypropionyl) -N-isopropylamino) phenyl; 4-N-ethyl-N- (2-methoxyethyl) amino) phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4piperidinylfenyl; 4-pyridylphenyl; 4-pyrolidinylfenyI; 4-t-butylacrylphenyl; 5 (dimethylamino) thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3dinietylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6 (N-methyl-N-formylamino) -3-pyridinyl; 6- (N-methyl-N- (2-methoxyethyl) amino) -3pyiidinyl; 6- (2-oxo-oxazolidinyl) -3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidines 1-3-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- (Nfenylmetoxykarbonyl) aminophenyl; 2- (3-bromophenyl) ethyl, 2- (3-cyanophenyl) methyl;

2- (4-bromophenyl) ethyl; 2- (5-chloro-2- (thiophen-3-yl) phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl;

3- (furan-2-yl) phenyl; 3- (thiophen-2-yl) phenyl; 3- (2-pyridyl) phenyl; 3- (319 methoxybenzyl) phenyl; 3- (amino) propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3brómfenylmetyl; 3carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3dietylmalonylalylfenyl; 3-dimethylamino-phenyl; 3-ethoxyphenyl; 3-fluoro-5trifluórmetylfenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxy-ethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl;

3- t -butylacrylphenyl; 3-trifloromethyoxyphenyl; 3-trifluoromethylphenyl; 3vinylpyridinylfenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl;

3,4,5-trimethoxyphenyl; 3,5-di (trifluoromethyl) phenyl; 3,5-dibromophenyl; 3,5dichlorophenyl 1; 3,5-dimethoxyphenyl; 3,5-dimethyl-phenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyfenyI; 4-bromophenyl; 4-bromo-thiophen-2-yl; 4butoxyfenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl;

4-neopentylphenyl; 4-phenoxyphenyl; 5-bromo-thiophen-2-yl; 5-cykloliexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl or other groups as specified herein.

The term acyl, as used herein, refers to a carbonyl bonded moiety such as a lower alkyl-carbonyl or aryl-carbonyl, wherein the lower alkyl and aryl are as defined herein. Examples of acyl include, for example, acetyl, propionyl, hexanoyl, trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N-Bocglycylimidazoyl, N-phthalimidylglycyl and the like. or other than specified herein.

The term aryl or substituted aryl as used herein refers to a carbocyclic aromatic radical including, for example, phenyl and 1-naphthyl or 2-naphthyl, which may be unsubstituted or substituted independently by substituting one, two or three hydrogen atoms for Cl, Br, F, 1, cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, amino, lower alkylamino, di (lower alkylamino), N-lower alkyl, N-lower alkoxyamino, trifluoromethyl or methoxymethyl. In addition, the term aryl refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lower alkoxy, phenyl-lower alkenyl 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-carboxaniidopropylphenyl or others as shown herein.

The term "arylalkyl" refers to a lower alkyl radical having attachment to an aryl group as defined above, such as benzyl and phenylethyl.

The term "aryloxy" refers to an aryl radical that is attached to the molecule through an ether bond (namely, through an oxygen atom) such as, for example, phenoxy, naphthyloxy, 4-chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.

The term "cycloalkyl" refers to a cyclic, saturated hydrocarbon radical having from three to seven ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C 3 -C 8 cycloalkyl.

The term "cycloalkyl-lower alkyl" refers to a lower alkyl radical, as defined below, substituted with a cycloalkyl group, as defined above, by replacing one hydrogen atom. Examples of cycloalkyl-lower alkyl include cyclopropylmentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.

The term "heteroaryl" refers to a monocyclic, aromatic radical having from five to seven ring atoms, of which one is nitrogen, oxygen or sulfur; none, one or two atoms are other heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, a radical that is linked to the remainder of the molecule via any ring atoms. The heteroaryl group may be unsubstituted or substituted by independently replacing one, two, or three hydrogen atoms with Cl, Br, F, 1, cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, amino, lower alkylamine, di (lower alkylamine), N-lower alkyl-N-lower alkoxy xylamine, trifluoromethyl or methoxymethyl. In addition, the term "heteroaryl" refers to a heteroaryl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-lower alkoxy, phenyl-lower alkenyl or cycloalkyl-lower alkyl group. In addition, a heteroaryl group may be substituted by replacing any two adjacent hydrogen atoms with a grouping of atoms to form a fused benzene ring. Examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, 5-methylthiophen-2-yl, 5-nitrothiophen-2-yl, 5-methylfuranyl, benzofuranyl, benzofuranyl , benzothiophenyl, and the like. and others as shown here.

The term "heterocyclic group" refers to a saturated or unsaturated monocyclic ring radical having from four to seven ring atoms, of which one is nitrogen or oxygen; one or two ring atoms are other heteroatoms independently selected from S, O and N; and the remainder are carbon atoms, a radical that is attached to the remainder of the molecule through any ring atoms and which is optionally substituted on either the nitrogen or carbon atom with another radical selected from the group consisting of aryl (lower alkyl), alkoxycarbonyl, lower alkyl, halogen ( lower alkyl), amino (lower alkyl), hydroxy-substituted lower alkyl, hydroxy, lower alkoxy, halogen, amino, lower alkylamino and amino, (lower alkyl) amino or alkanoylamino having from one to eight carbon atoms, wherein the amino group may be further substituted with an alkanoyl of from one to eight carbon atoms, an α-amino acid, or a polypeptide. Examples of the heterocyclic group include pyrrolidine, tetrahydrofuran, dihydropyrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine, and azetidine, and those additionally described herein.

The term "heterocyclic-lower alkyl" refers to an 11a lower alkyl radical, as defined below, substituted with a heterocyclic group, as defined above, by replacing one hydrogen atom. Examples of cycloalkyl-lower alkyl include pyrrolidinylmethyl, piperidinylethyl, and the like.

The term "lower alkyl" as used herein refers to a saturated, straight or branched chain hydrocarbon radical containing from one to six carbon atoms inclusive, which may be unsubstituted or substituted by an independent replacement of one, two or three carbon atoms with C1, Br groups , F, 1, cyano, carboxamido, hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkylamino) or N-lower alkyl-N-lower alkyloxyamino. Examples of lower alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, t -butyl, ZzZ-butyl, neopentyl, z-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, and the like. In certain instances, the "C 1 -C 6 alkyl" group is described and has a similar meaning as described above for lower alkyl, but is more specifically indicated. Similarly, the term "CoCealk-yl" indicates carbon atoms that may be present in the alkyl chain, including the desired carbon atom. These terms also refer to an 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 a mono-unsaturated straight or branched chain hydrocarbon radical containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, t -butenyl, z-butenyl, zz- pentenyl and z-hexenyl. These variables are also referred to as C 1 -C 6 alkenyl.

The term "lower alkoxy" refers to a lower alkyl radical that is attached to the molecule via an ether bond (namely, through an oxygen atom) such as methoxy, ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, an ezz-butoxy group, a pentyloxy group, a hexyloxy group, their isomeric forms and the like. This term is also described as C 1 -C 6 alkyloxy

The term "lower alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical having a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, zi-petnynyl, and zz-hexynyl. This term is also described as C 2 -C 6 alkynyl.

The term "mammal" has its normal meaning and includes humans.

In a further aspect of the present invention there are provided pharmaceutical compositions comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier.

• I

The present invention includes one or more compounds as mentioned above formulated in formulations together with one or more non-toxic, physiologically compatible or acceptable diluents, carriers, excipients or vehicles, collectively referred to herein as diluents for parenteral injection, for oral applications in solid or liquid form, for rectal or topical applications, and the like. as well known in the art, the compound of the present invention may exist in various forms including pharmaceutically acceptable salts, amides and the like.

The formulations may be prepared by administering the exact amount of the compound or compounds of the invention. The following dose controls are intended

I 's to provide optimal therapy, i.v. infusion: 0.1-250 nmol / kg / min, preferably from 1-50 nmol / kg / min; orally: 0.01-250 μΜοΙ / kg / day, preferably from about 0.1-50 μΜοΙ / kg / day; these oral molar dose ranges correspond to 0.005-125 mg / kg / day, preferably 0.05-25 mg / kg / day. For the treatment of acute disorders, intravenous drug delivery is preferred; the oral treatment of chronic disorders with a tablet or sustained release formulation is preferred.

"Pharmaceutically acceptable amide" refers to pharmaceutically acceptable, non-toxic amides of the compounds of the present invention, which include amides formed with suitable organic acids or amino acids, including short peptides consisting of one to six amino acids linked by amide bonds that may be branched or linear wherein the amino acids are independently selected from naturally occurring amino acids such as glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine , histidine, ornithine, and the like.

The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable, non-toxic, inorganic or organic acid addition salts of the compounds of the present invention, as described in more detail below.

The term "substituted version thereof" refers to those generic groups ^1, such as aryl or heteroaryl or heterocyclic group, having substituents around an aryl, heteroaryl, heterocyclic group or other types that are varied in chemically acceptable positions and are named or explained herein examples.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, fumarate, fumarate, fumarate, fumarate , heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, i

methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.

Suitable cationic salts are readily prepared by conventional procedures such as reacting an acid of formula (1) with a suitable amount of a base such as an alkali or alkaline earth metal hydroxide such as sodium, potassium, lithium, calcium or magnesium or an organic base such as an amine such as dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, or the like, or with a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, nitrogen-containing basic groups can be quaternized with such agents as a lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl; long chain Balogenides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others Water or oil-soluble or dispersible products are thus obtained.

The salts of the present invention can be synthesized from compounds of formula (I) or (II) which contain basic or acidic moieties by conventional methods such as reaction of the free base or acid with stoichiometric amounts or excess of the desired inorganic acid-forming salt or base in a suitable solvent; in various combinations of solvents.

in

Also included within the scope of the present invention are pharmaceutical compositions comprising one or more compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carrier carriers in the method described below.

Formulations suitable for parenteral injection may contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile dusts for reconstitution into sterile injectable solutions or dispersions, suspensions or emulsions and sterile dusts. 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 injectable organic esters such as ethyl oleate. The intrinsic fluidity can be maintained, for example, by the use of a lecithin coating, in the case of dispersion by the maintenance of the desired particle size, and by the use of surfactants.

These formulations may also contain adjuvants that protect, wet, emulsify and disperse agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugar, sodium chloride and the like. Prolongation of the absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, by aluminum monostearate and gelatin.

If desired, and for more efficient distribution, the compounds may be incorporated into slow release or target delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents into sterile solid preparations which may be dissolved in sterile water or any other sterile injectable medium immediately prior to use.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one conventional inert vehicle (or carrier) such as sodium citrate, dicalcium phosphate and additionally (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and orthosilicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gelatin;

(c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, a certain complex of silicates, and calcium carbonate; (e) solution inhibitors such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin, bentonite; and (i) lubricants such as talc, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents.

Solid compositions of a similar type may be used as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar as well as high relative molecular weights of 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 other well known in the art. Solid dosage forms may contain pacifying agents and may be free of formulations that release the active compound or compounds in some part of the intestinal tract to some extent delayed. Examples of embedding compositions that can be used are polymeric substances and waxes.

The active compound may also be in microencapsulated form, if appropriate, with one or more of the above carriers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germination oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures thereof, and the like.

In addition to such inert diluents, these liquid dosage forms may also include excipients such as wetting agents, emulsifying and suspending agents, liming neutralization, flavoring agents and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures thereof, and the like.

Formulations for rectal or vaginal applications are preferably laces 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 wax suppositories, which are solid at ambient temperature but liquid at body temperature and therefore they dissolve in the rectum or vaginal cavity and release the active components.

Dosage forms for topical and transdermal administration of a compound of this invention further include ointments, pastes, creams, liquid forms for external use, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration through a transdermal patch is the least effective and preferred dosage form of the present invention. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffer 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 natural form may require admixture with a specially formulated composition or specially filled material to ensure proper delivery of the dose. In addition, compounds that are rapidly absorbed through the skin may require formulations with absorption by the retardants or barriers. Ophthalmic formulations, eye ointments, dusting powders and solutions are intended to be within the scope of this invention.

The present compounds may also be administered in the form of liposomes as known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by inonolamellar 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 present liposome formulations may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. For example, see Prescott, Ed., Methods in CeH Biology, Volume XIV, Academic Press, New York, N.Y. (1976), page 33, el seq.

Synthetic methods

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes 1 and 2, which illustrate the methods by which the compounds can be prepared. The substituent groups R ¹ , R ² , R 1 and R ⁴ are as defined above unless otherwise stated.

Scheme 1

In accordance with Scheme 1, compounds of formula (II) are prepared wherein R ¹ and R ² are hydrogen. The starting material 4,6-diamino-5-iodopyrimidine (1) is reacted with an ethenylboronic acid derivative (2) in which the substituent R 'is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or substituted versions thereof, in the presence of tetrakistriphenylphosphine palladium or other suitable palladium-aqueous alkali metal or potassium bicarbonate complex, for example preferably buffered with aqueous sodium or potassium bicarbonate at reflux for about 8 hours to about 24 hours to prepare compound (3). Compound (1) can be prepared from 4,6-diaminopyridine by reaction with iodine in DMF at a temperature of about 40 ° C to about 50 ° C for about 24 hours in the presence of potassium carbonate. A compound of formula (2) can be prepared by reacting R ^J substituted acetylene with catecholborane in a solvent such as THF. R'-substituted-acetylenes can be prepared according to various literature procedures such as Van Hijfte et al. al, Tetrahedron Letters, 1989, 30, 3655; Tao et al. J. Org. Chem., 1990, 55, 63; and Rossi et al., Gazz. Chim Ital., 1990,120; 783-791.

Compound (3) is then reacted with an aldehyde compound (4) wherein R ⁴ is an aryl, heteroaryl or heterocyclic group to prepare compound (5) in a suitable anhydrous solvent, under Suzuki reaction conditions such as diphenyl ether, 2,4-trichlorobenzene, toluene, and the like, in the presence of 4 A molecular sieve filters to adsorb water from the reaction at reflux for about 2 to about 24 hours. Compounds (5) are compounds of formula (II) wherein R and R are hydrogen. The compounds prepared according to Scheme 1 can further be reacted with a suitable reducing agent such as hydrogen in the presence of a catalyst or other reducing agent to give 5.6 and / or 7.8 reduced versions of the compound of formula (II). In addition, the reduction can take place to form single bonds at positions 5,6 and 7,8 and double bonds between carbon 6,7. In the previous case (s), stereoisomers are formed and are also included within the scope of the invention. These isomers can be isolated by conventional means.

Scheme 2

In accordance with Scheme 2, compounds of formula (II) wherein one or both of R ¹ and R ² are lower alkyl, arylalkyl or acyl may be prepared by reacting compound (5) with a suitable reagent. It is possible to prepare the desired derivative of a compound of formula (1) wherein R ¹ and R ² are both hydrogen atoms from a compound of formula (1) or (II) wherein R ¹ and R ² are not both hydrogen atoms When R ¹ or R ^{2 is} lower alkyl, the preparation of compounds may be achieved by reacting the free amino group with a suitable alkylating agent such as an alkyl halide, alkyl methanesulfonate or alkyl p-toluenesulfonate in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent such , such as methylene chloride or THF. When R ¹ or R ^{2 is} acyl, the preparation of the compounds can be achieved by reacting the free amino group with a suitable, for example, arylalkyl halide, alkyl methanesulfonate or alkyl p-toluenesulfonate, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent such as methylene chloride. or THF. When the substituent R ¹ or R ^{2 is an} arylalkyl, the preparation of compounds can be achieved by reacting the free amino group with a suitable acid anhydride, an acyl halide such as acyl chloride, or an activated acyl group such as acyl cyanide, acylazide or thiolester in the presence of a base such as triethylamine or carbonate potassium in a suitable solvent such as methylene chloride or THF. When R ¹ and R ^{2 are} joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom, the compound may be prepared by reacting a precursor having a halogen atom instead of the amino group at position 4 with a compound of five to seven membered ring optionally containing an additional oxygen or nitrogen atom. Examples of such compounds include, but are not limited to, morpholine, piperidine, pyrrolidine, piperazine, thiomorpholine, and the like. Also, this alternative process can be used to prepare alkyl substituted amino compounds by, for example, reacting chloro compounds with a monosubstituted or disubstituted amine such as diethylamine, allylamine, dibutylamine. This reaction is readily accomplished in a solvent such as methylene chloride in the presence of a tertiary amine. A precursor having a halogen atom in place of the amino group at position 4 can be prepared by substituting 6-amino-4-chloro-5-iodopyrimidine for

4,6-diamino-5-iodopyrimidine (Compound (1) Scheme 1) followed by Scheme 1.

A method of inhibiting kinases

In another aspect of the present invention, there is provided a method of inhibiting adenosine kinase. Accordingly, the adenosine kinase enzyme is exposed to an effective inhibitory amount of an adenosine kinase inhibitor compound of the present invention. Such preferred compounds for use in this method are the same as those already mentioned. Means for determining an effective inhibitory amount are well known in the art.

The adenosine kinase can be localized in vitro, in situ or in vivo to be inhibited. Where the adenosine kinase is localized in vitro, it is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radioisotope-labeled adenosine substrate, magnesium chloride, and ATP. The enzyme may exist in intact, cells or isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under appropriate physiological conditions. Means for determining maintenance times are well known in the art and depend, among other things, on enzyme concentrations and physiological conditions. Suitable physiological conditions are those necessary to maintain the viability of adenosine kinase and include temperature, acidity, toxicity, and the like. Inhibition of adenosine kinase can be performed, for example, according to standard procedures well known in the art (Yamada eZ al., Comp. Biochem. Physiol. 1982, 71B: 367-372).

Where adenosine kinase is localized in situ / m or in vivo, it is typically applied to liquid perfused tissue containing the enzyme. The fluid may be a naturally occurring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution, and the like. The process of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administration of the inhibitor compound is typically accomplished by parenteral (e.g., intravenous injection or oral) administration of the compound. An effective inhibitory amount or an effective therapeutic amount is applied.

By "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat or ameliorate the respective disorders of adenosine kinase or those diseases or conditions that are ameliorated by inhibiting adenosine kinase and increasing adenosine levels, at a reasonable benefit / risk ratio applicable to any medical treatment. More or less, it is clear that the overall daily use of the compounds and compositions of the present invention is at the discretion of the attending physician based on sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on various factors including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the use of the specific formulation, the age, body weight, overall health, gender and diet of the patient, time of administration, method. application and rate of excretion of the specific compound used, duration of treatment; administration of drugs in combination or identity with the specific compound used and similar factors well known in the medical art and the ability of the attending physician.

The compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any standard procedures well known in the art. For example, cells containing adenosine kinase such as human neuroblastoma IMR-32 cells are cultured in the presence and absence of inhibitor. Inhibition is measured as the ability to inhibit the phosphorylation of endogenous or externally applied ¹⁴ Cadenosine by these cells. Cells may be intact or disrupted. The specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on the adenosine A1 and A 2a receptor binding, on adenosine deaminase activity and on adenosine transport.

The compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo. Several animal models for studying adenosine kinase activity and the effects of inhibiting such activity are well known in the art. An example is adenosine kinase inhibitors that have been reported to protect rodents (e.g., mice and rats) from seizures induced by subcutaneous administration of pentylenetetrazole (PTZ). Typically, rodents are injected with various doses of the administered inhibitor administered at different times, by subcutaneous administration from about 10 to about 500 milligrams per kilogram of PTZ. The injected animals are then observed from the onset of the seizures.

The compounds of the invention were tested in an in vivo hot plate assay for the analgesia of mammals such as mice. For example, the compounds of Examples 55, 103 and 104, in the procedure also described below, were tested 30 minutes after pretreatment by administration of the drug (30 μιηοΐ / kg i.p.) for tenth jump latency (in seconds). The longer the number of seconds, the more effective the administration of the drug is to mask the pain felt by the hot plate. Compound 55 resulted in 132.86 seconds related to the vehicle alone, which was 72.76 + 10.51 seconds. Compound 103 resulted in 103.29 seconds. Compound 104, when tested, resulted in insignificant 62 44 seconds and will be retested in other pain models. The compounds of the invention are therefore potent pain relievers as well as adenosine kinase inhibitors as demonstrated in this animal model and the additional investigations described below.

Examine the mouse in a hot plate test

Male CF1 mice (Charles River) of approximately 25-30 g body weight are pretreated with 10 ml / kg test compounds, i.p. or p.o., in groups of 8 animals per dose. At the end of the pre-treatment, the mice are placed in an individual "Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor" (Columbus, OH; Model AHP16AN), 9.8 x 7.2 x 15.3 cm (length x width x height) plastic fencing on top of copper plate heated to 55 ° C. The infrared sensors located near the top of each enclosure detect beam intersections that occur when the mice do not touch the heated surface Latency times for each jump are automatically recorded, and latencies for the first and tenth leaps are used to analyze the data. Mice that do not meet the 10 jumps criterion in 180 seconds are immediately moved from the hot plate to avoid tissue damage and are assigned a maximum value of 180 seconds as their latency for the tenth jump.

Several other animal models of adenosine kinase activity have been described [See, for example, Davies et al., Hmchem. Harmacol., 33: 347-355 (1984); Keil e! al .. Eur. ./. Pharmacol., 271: 37-46 (1994); Murray, et al., Dmg Developmenl Res., 28: 410-415 (1993)].

Several inhibitor compounds of the present invention have been tested in vitro and have been found to inhibit adenosine kinase activity. The results of some representative studies are shown in Table 1 below. The data show that the compounds inhibit adenosine kinase.

Table 1

Adenosine kinase inclusion accomplished by representative compounds of the invention

Compounds of Example No Cause (nM) 2 73- 3 185 6 467 9 115 10 317 15 1 1 36 250 38 45 55 5 59 1 17 62 30 '63 200 78 25 98 95 103 » 3 J 104 8

A method of treating cerebral ischemia. epilepsy, nociperption (nociception) (pain). inflammation, including such conditions as septic shock due to septic infection

In another aspect of the present invention, there is provided a method of treating cerebral ischemia, epilepsy, nociperception or nociception, pain, inflammation including conditions such as septic shock due to septic infection in humans or lower mammals, comprising administering to the mammal a therapeutically effective amount of the compound.

Changes in the cellular activity of adenosine kinase have been observed in certain disorders. Adenosine kinase activity has been found to decrease, relative to normal liver, in various rat hepatomas; enzyme activity giving a negative correlation with the rate of tumor growth (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also reduced in liver regeneration after partial hepatectomy in experimental animals (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). It has been found that adenosine erythrocyte adenosine activity is reduced in gout patients. (Nishizawa, et al., Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with human immunodeficiency virus (HIV) presenting with symptoms of AIDS and was increased in asymptomatic HIV seropositive and HIV seronegative high-risk subjects compared to normal healthy controls (Renouf, et al.). 1989, 35: 1478-1481). It has been suggested that measurement of adenosine kinase activity is useful to demonstrate in monitoring the clinical development of patients with HIV infection (Renouf, et al., Clin. Chem. 1989, 35: 1478-1481). Septic infection may lead to systemic inflammatory syndrome (SIRS) characterized by increased cytokine production, neutrophil accumulation, hemodynamic effects, and tissue damage or death. The ability of an adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated in improved symptoms of the syndrome, during the known anti-inflammatory effects of adenosine (Firestein, et al., J. of Immunology, 1994, 5853-5859). Adenosine kinase inhibitors are expected to be able to elevate adenosine levels and alleviate pain conditions, as it has been demonstrated that administration of adenosine or an analog thereof results in antinociception or antinociperception (Swaynok, et al., Nenroscience, 1989, 32: No.3,557 -569).

The following examples of compounds and procedures illustrate preferred embodiments of the present invention and do not limit the scope of the invention, which is fully defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-amino-6-phenyl-7- (p-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine

A sample of 4,6-diamino-5- (2-phenylethenyl) pyrimidine (150 mg) was suspended in 10 mL of phenylether with 1.2 equivalents of 4- (dimethylamino) benzaldehyde (reagent "R ⁴ ") and 1.5 g 4 And the molecular site. Heat the solution at 170 ° C for 4 hours, then cool and remove the solvent. The residue is purified by column chromatography to give the desired compound. IR (infrared spectroscopy) (KBr) 3325, 1589, 1555, 1400, 1340, 1196, 819 cm ^-1 ; MS (mass spectroscopy) m / z 342 [M + H] &lt; ^{+ &gt};.

4,6-Diamino-5- (2-phenylethenyl) pyrimidine was prepared as follows:

Ia. 5 \ iodo-4,6-diaminopyrimidine

4,6-Diaminopyrimidine hemisulphate monohydrate (26.13 g, 147.5 mmol, Aldrich) and K ₂ CO 3 (30.58 g, 221.3 mmol) are suspended in water (400 mL). To this suspension was added a solution of iodine (41.19 g, 162.3 mmol) in DMF (100 mL). The mixture was heated at 45 ° C for 23 hours. After cooling, a 2M solution of Na ₂ S ₂ O ₃ (15ml) was added to the cooled excess iodine. The white product was then collected, washed with water (3 x 20 mL) and dried under high vacuum to give 33.1 g of the desired compound (90%).

lb. 2-phenylethenylboronic acid (reagent "R ^J ")

Phenylacetylene (5 mmol, Aldrich) was dissolved in 5 mL dry THF and added dropwise catheter boronate (5 mL, 1 M in THF, Aldrich) at 0 ° C. The solution is heated to reflux for 1.5 hours and the solvent is taken immediately to the next step.

c. 4,6-diamino-5- (2-phenylethenyl) pyrimidine

To a solution of 5-iodo-4,6-diaminopyrimidine (1 mmol, from step 1 above) in 50 mL of dioxane was added 2-phenylethenylboronic acid (5 mmol), 5% Pd (PPh ₃ ) ₄ and 1M Na ₂ CO 3 (10 ml). The reaction mixture was heated for 12 hours. The solvent was removed in vacuo and the residue was diluted with water and extracted with CH ₂ Cl ₂ (3 x 30 mL). The organic layer was concentrated under reduced pressure and the residue was dried under high vacuum. The crude mixture was analyzed by column chromatography (using 5% MeOH, CH ₂ Cl 2 as eluent) to give the desired compound MS m / z: 213 (M + H) ⁺ .

Examples 2-107

Following the procedures of Example 1 other than the substituted reagents to updated in Table 1 below for the ^R4 reagent, and ^R? of Example 1, the compounds of Examples 2-107 were prepared.

v c. P ^r · · ,. Title reagent R ⁴ (position 7) reagent R ³ (position 6) Data 2 4-amino-6- (4- methylphenyl) -7- (4- dimethylamino) phenyl l) pyrido [2,3-d] pyrimidine 4 (Dimethylamino) - benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR (KBr) 3360, 1660, 1600, 1185, cm -1; MS m / z 356 [M + H] ⁺ . 3 ^1- 4-Amino-6- (4- (dimethylamino) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine 4 (Dimethylamino) - benzaldehyde 2- (4- dimethylaminophenyl) ethenylboronic acid IR (microscope) 3325, 1608, 1589, 1560, 1520, 1400, 1358, 1340, 1196, 818 cm ^-1 : MS m / z 385 [M + H] +. 4 4-Amino-6- (4-methylphenyl) -7-phenylpyrido [2,3-d] pyrimidine benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR (microscope) 3325, 1659, 1553, 1340, 1340, 821 cm ^-1 : MS m / z 313 [M + H] +.

5 4-amino-6- (4- methylphenyl) -7- (4- bromo-phenyl) -pyrido [ 2,3-d] pyrimidine 4-brómbenzal- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR (microscope) 3325, 1600, 1553, 1340, 1340, 818 cm ^-1 ; MS m / z 391 [M + H] +. · 6 4-amino-6- (4- (Dimethylamino) phenyl yl) -7- (4- pyridinyl) pyrido [2 , 3-d] pyrimidine pyridin-4- carboxaldehyde 2- (4- dimethylaminophenyl) ethenylboronic acid IR (microscope) 3320, 1608, 1560, 1521, 1410, 1344, 818 cm ^-1 ; MS m / z 343 [M + H] &lt; + &gt;. 7 4-amino-6- (4- (Dimethylamino) phenyl yl) -7- (4- bromo-phenyl) -pyrido [ 2,3-d] pyrimidine 4 bromobenzaldehyde 2- (4-dimethylacetamide minofenyl) - ethenyl-boronic acid acid IR (microscope) 3320, 1606, 1562, 1547, 1520, 1340, 1010, 818 cm ^-1 ; MS m / z 420 [M + H] + · 8 4-amino-6- (4- methylphenyl) -7- (4- (5-pyrimidinyl) phenyl) pyrido [2,3- d] pyrimidine 4- (5- pyrimidinyl) benzamide aldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3360, 160, 1600, 1555,  1410, 1345, 820; MS m / z 391 [M + H] +. 9 4-amino-6- (4- methylphenyl) -7- (4- (2- (2-pyridinyl) ethenyl) phenyl) pyridine [2,3-d] pyrimidine 4- (2- (2- pyridyl) ethenyl) benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3400, 3320, 3160, 3040, 1595, 1560, 1340; MS m / z 416 [M + H] +. 10 4-Amino-6- (4-methylphenyl) -7- (3-pyridinyl) pyrido [2,3-d] pyrimidine 3-pyridínkarbox- aldehyde 2- (4-methylphenyl) ethenyl) boronic acid IR 3320, 3360, 3040, 1640, 1550, 1340, 815; MS m / z 314 [M + H] +. 11 4-Amino-6- (4-methylphenyl) -7- (thiophen-3-yl) pyrido [2,3-d] pyrimidine 3-tiofenkarbox- aldeliyd 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3440, 3320, 3,160, 3,100, 1600, 1555, 1335, MS m / z 31 (M + H) +. 12 4-amino-6- (4- methylphenyl) -7- (Thiophen-2- yl) pyrido [2,3- d] pyrimidine 2-tiofenkarbox- aldeliyd 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3460, 3 60, 33 10, 3100, 1600. 1555, 1425; MS m / z 319 (M + H) &lt; + &gt;.

13 4-amino-6- (4-me- butylphenyl) -7- (2-pyrene piperidinyl) pyrido [2,3- pyrimidine 2-pyridínkarbox- aldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3440, 3320, 3170, 1640, 1600, 1555, 1340; MS m / z 314 (M + H) &lt; ^{+ &gt};. 14 4-amino-6- (4-me- butylphenyl) -7- (3,4- metyléndioxyfe- phenyl) pyrido [2,3- pyrimidine • 3,4- metyléndioxyben zaldehyd 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3365, 3120, 1600, 1555, 1440, 1250, 1040; MS m / z 357 (M + H) &lt; - &gt; 15 4-amino-6-butyl 7- (thiophen-2- yl) pyrido [2,3- d] pyrimidine 2-tiofenkarbox- aldehyde 1-hexenylboronic acid IR 3320, 3160, 2955, 2860, 1640, 1560, 1335; MS m / z 285 (M + H) &lt; ^{+ &gt};. 16 4-Amino-6-butyl-7- (thiophen-3-yl) pyrido [2,3d] pyrimidine 3-tiofenkarbox- aldehyde 1-hexenylboronic acid IR 3300, 3070, 2950, 2850, 1600, 1565, 1330; MS m / z 285 (M + H) &lt; ^{+ &gt};. 17 4 AminQa 4-6- (4- methylphenyl) -7- (5- bromo-thiophen-2- yl) pyrido [2,3- d] pyrimidine 5-bromothiophene-2- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3450, 3300, 3100, 1640, 1600, 1555, 1425; MS m / z 397/399 (M + H) &lt; ^{+ &gt};. 18 4-amino-6- (4- methylphenyl) -7- (5- methyl-thiophen-2- yl) pyrido [2,3- d] pyrimidine 5-methyl-thiophene-2- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3460, 3380, 3300, 3 150, 1640, 1555, 1445; MS m / z 333 (M + H) &lt; ^{+ &gt};. 19 4-amino-6- (4- methylphenyl) -7- (4- trifluoromethoxy) females yl) pyrido [2,3- d] pyrimidine 4 (a trifluoromethyl tulle) benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3440, 3320, 3180, 1555, 1490, 1340, 820; MS m / z 397 (M + H) &lt; ^{+ &gt};. 20 4-amino-6- (4- methylphenyl) -7- (3- phenoxyphenyl) pyridine [2,3-d] pyrimidine 3-fenoxybenz- aldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3400, 3180, 3050, 1555, 1340, 1255, 820; MS m / z 405 (M + H) &lt; ^{+ &gt};.

21 4-amino-6- (4- methylphenyl) -7- (5- nitro-thiophen-2- yl) pyrido [2,3- d] pyrimidine 5-nitro-thiophen-2- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3380, 3100, 1595, 1550, 1330, 1260, 815; MS m / z 364 (M + H) &lt; ^{+ &gt};. 22 4-Amino-6- (4-me- butylphenyl) -7- (4- bromo-thiophen-2- yl) pyrido [2,3- d] pyrimidine 4-bromo-thiophen-2- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3320, 3100, 1595, 1555, 1415, 1340, 820; MS m / z 397/399 (M + H) &lt; ^{+ &gt};. 23 4-amino-6- (4- methylphenyl) -7- (3- methyl-thiophen-2- yl) pyrido [2,3- d] pyrimidine 3-methyl-thiophen-2- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3300, 3060, 1600, 1550, 1450, 1335, 820; MS m / z 333 (M + H) &lt; ^{+ &gt};. 24 4-amino-6- (4- methylphenyl) -7- (Furan-2- yl) pyrido [2,3- pyrimidine furan-2 carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3430, 3300, 3170, 1630, 1560, 1450, 1340; MS m / z 303 (M + H) &lt; ^{+ &gt};. 25 4-amino-6- (4- methylphenyl) -7- (Furan-3- yl) pyrido [2,3- pyrimidine furan-3- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3360, 3140, 1655, 1605, 1555, 1340, 1165; MS m / z 303 (M + H) &lt; ^{+ &gt};. 26 4-amino-6- (4- methylphenyl) -7- (5- methyl-furan-2- yl) pyrido [2,3- d] pyrimidine 5-methylfuran-2- carboxaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3460, 3320, 3160, 2960, 1600, 1555, 1330, 392; MS m / z 37 (M + H) ⁺ . 27 4-amino-6- (4- (2- propyl) phenyl) -7- (Thiophen-2- yl) pyrido [2,3- pyrimidine thiophene-2- carboxaldehyde 2- (4- (2- propyl) phenyl) - ethenyl-boronic acid acid IR 3440, 3180, 1630, 1600, 1555, 1335, 820, MS m / z 3 17 (M + H +). 28 4-amino-6- (4- (2- propyl) phenyl) -7- (5-nitro-thiophen-2- yl) pyrido [2,3- d] pyrimidine 5-nitro-thiophen-2- carboxaldehyde 2- (4- (2- propyl) phenyl) - ethenyl-boronic acid acid IR 3380, 3160, 2960, 1635, 1600, 1555, 1330; MS m / z 392 (M + H) &lt; ^{+ &gt};.

29 4-amino-6- (4- methylphenyl) -7- (5- nitro-thiophen-2- yl) pyrido [2,3- pyrimidine 5-nitro-thiophen-2- carboxaldehyde 2- (4-methylphenyl) ~ ethenyl-boronic acid acid IR 3330, 3160, 1630, 1600, 1555, 1350, 810; MS m / z 348 (M + H) &lt; ^{+ &gt};. 30 4-amino-6- ^(4-1 (dimethylamino) phen yl) -7- (thiophen-2-yl) -pyrido [2,3-pyrimidine thiophene-2- carboxaldehyde 2-Í4- (dimethylamino) phenyl) -ethenylboronic acid IR 3440, 3160, 1610, 1555, 1525, 1340, 820; MS m / z 348 (M + H) &lt; ^{+ &gt};. 3 1 4-amino-6- (3,4- dimethoxyphenyl) -7- (Thiophen-2- yl) pyrido [2,3- d] pyrimidine thiophene-2- carboxaldehyde 2- (3,4- dimethoxyphenyl) - ethenyl-boronic acid acid IR 3420, 3080, 1600, 1560, 1515, 1425, 1340; MS m / z 365 (M + H) &lt; ^{+ &gt};. 32 4-amino-6- (3,4- dimethoxyphenyl) -7- (5-nitro-thiophen-2- yl) pyrido [2,3- d] pyrimidine 5-nitro-thiophen-2- carboxaldehyde 2- (3,4- dimethoxyphenyl) - ethenyl-boronic acid acid IR 3420, 2840, 1600, 1555, 1515, 1335, 1255; MS m / z 410 (M + H) &lt; ^{+ &gt};. 33 4-Amino-6-hexyl-4- (4- ') (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4 (Dimethylamino) - benzaldehyde 1-Octenylboronic acid IR 3320, 3100, 2920, 2850, 1600, 1560, 1335; MS m / z 350 (M + H) ^4th 34 4-amino-6-hexyl- 7- (thiophen-2- yl) pyrido [2,3- d] pyrimidine thiophene-2- carboxaldehyde 1-Octenylboronic acid IR 3320, 3160, 2920, 2840, 1600, 1560, 1425; MS m / z 313 (M + H) &lt; ^{+ &gt};. 3 5 4-amino-6- (2- methyl-2-propyl) - 7- (thiophen-2- yl) pyrido [2,3- pyrimidine thiophene-2- carboxaldehyde 3,3-Dimethyl-1 butenyl- boronic acid IR 3400, 3320, 3180, IR 2960, 1640, 1565, 1335; MS m / z 285 (M + H) &lt; ^{+ &gt};. 36 4-amino-6- (4- (2- propyl) phenyl) -7- (4- (dimetylami- amino) phenyl) pyrido [2, 3-d] pyrimidine 4- (dimethylamino) -benzaldehyde 2- (4- (2- propyl) phenyl) - ethenyl-boronic acid acid IR 3600-3250, 2955, 1590, 1555, 1400, 1340, 1195, 815, MS m / z 384 (M + H) ⁺ .

37 4-amino-6- (4- propyl-phenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 1 2- (4- propyl-phenyl) - ethenyl-boronic acid acid 1 IR 3520-3250, 2960, 1590, 1555, 1400, 1340, 1195, 815; MS m / z 384 (M + H) &lt; ⁺ &gt; ^. 38 4-amino-6- (3,4- dimethoxyphenyl) -7- (4- (dimetylami- amino) phenyl) pyrido [2, 3-d] pyrimidine 4 (Dimethylamino) - benzaldehyde 2- (3,4- dimethoxyphenyl) - ethenyl-boronic acid acid IR 3320, 32402760, 1590, 1560, 1510, 1515, 1340; MS m / z 820 (M + H) &lt; ^{+ &gt};. 39 4-amino-6- (3-me- toxyfenyI) -7- (4- (dimetylami- amino) phenyl) pyrido [2, 3-d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3-methoxyphenyl) -ethenylboronic acid IR 3365, 3220, 3250-2780, 1660, 1590, 1560, 1460, 1400, 1200, 820, MS m / z 402 (M + H) &lt; ^{+ &gt};. 40 4-amino-6- (3- bromophenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3-bromophenyl) - ethenyl-boronic acid acid IR 3400-3250, 3250-284, 1660, 1590, 1560, 1340, 1200, 820; MS m / z 420 (M + H) &lt; ^{+ &gt};. 41 4-amino-6- (3- fluorophenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3-fluorophenyl) - ethenyl-boronic acid acid IR 3520-2800, 1645, 1610, 1590, 1560, 1525, 1400, 1340, 1200, 820; MS m / z 360 (M + H) &lt; ^{+ &gt};. 42 4-amino-6- (3-trifluoromethylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3- trifluoromethylphenyl) -ethenylboronic acid IR 560, 3520, 3240-2840, 1660, 1590, 1560, 1400, 1340, 1,160, 1120, S10, 700; M S m / z 40 (M + H) +.

43 4-amino-6- (3- chloromethyl-phenyl) - 7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3-chlorophenyl) - ethenyl-boronic acid acid IR 3500-3280, 3200-2840, 1660-1590, 1560, 1395, 1370, 1340, 1200, 820; MS m / z 376 (M + H) &lt; ^{+ &gt};. 44 4-amino-6- (3,5- dichlorophenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3,5- dichlorophenyl) - ethenyl-boronic acid acid IR 3560-3280 3240-3300 1640 1590 1560 1400 1365 1340 1195, 820, 800; M S m / z 411 (M + H) &lt; - &gt; 45 4-amino-6- (3,4- methylenedioxyphenyl ) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3,4- methylenedioxyphenyl) -ethenylboronic acid IR 3600-3280, 3240-3000, 1595, 1560, 1400, 1195, 1040, 815; MS m / z 386 (M + H) &lt; ^{+ &gt};. 46 4-amino-6- (3,4- methylenedioxyphenyl ) -7- (thiophen-2- yl) pyrido [2,3- pyrimidine thiophene-2- carboxaldehyde 2- (3,4- methylenedioxyphenyl) -ethenylboronic acid IR 3430, 3300, 3170, 1630, 1595, 1575, 1450, 1425, 1035, 820; MS m / z 349 (M + H) &lt; ^{+ &gt};. 47 4-amino-6- (3- metoxykarbonylfe phenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3- methoxycarbonylphenyl) -ethenylboronic acid IR 3360, 3320, 3200-3000, 1720, 1660, 1595, 1560, 1400, 1340, 1200, 820; MS m / z 400 (M + H) ^4th 48 4-amino-6- (3- (2- propyl) phenyl) -7- (4- (dimetyIami- amino) phenyl) pyrido [2, 3-d] pyrimidine 4- (dimethylamino) -benzaldehyde 2- (3- (2- propyl) phenyl) - ethenyl-boronic acid acid IR 3520-3280, 3200-3000, 2960, 1590, 1555, 1395, 1340, 1195; MS m / z 384 (M + H) &lt; ^{+ &gt};.

49 4-amino-6- (4- (2- methyl-2- propyl) phenyl) -7- (4- (dimetylami- amino) phenyl) pyrido [2, 3-d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (4- (2-methyl-2- propyl) phenyl) - ethenyl-boronic acid acid IR 3500-3280, 3180, 2960, 1590, 1555, 1340, 1195, 820; MS m / z 398 (M + H) &lt; ^{+ &gt};. 50 4-amino-6- (4- fluorophenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (4-Fluorophenyl) ethenylboronic acid IR 3490, 3320, 3200-3000, 1590, 1555, 1400, 1340, 1195, 820; MS m / z 360 (M + H) &lt; ⁺ &gt; ^. 51 4-amino-6- (4- methoxyphenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- pyrimidine 4- (dimetyIami- no) benzaldehyde 2- (4- methoxyphenyl) - ethenyl-boronic acid acid IR 3370, 3320, 32003000, 1660, 1590, 1555, 1400, 1340, 1250, 1195, 815; MS m / z 372 (M + H) &lt; ^{+ &gt};. 52 4-amino-6- (3- (Phenylmethoxy) phenyl l) -7- (4- (dimethyl- amino) phenyl) pyridine [2,3-d] pyrimidine 4- (dimetylami- no) benzaldehyde 1 2- (3- (phenylmethoxy) phenyl) -ethenylboronic acid IR 3360, 3320, 320Q3000, 1665, 1590, 1560, 1400, 1195, 820; MS m / z 448 (M + H) &lt; ^{+ &gt};. 53 4-amino-6- (4- chlorophenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetyIami- no) benzaldehyde 2- (4-chlorophenyl) - ethenyl-boronic acid IR 3480-3320, 3200-3020, 1590, 1550, 1410, 1340, 1195, 815; MS m / z 376 (M + H) &lt; ^{+ &gt};. 54 4-amino-6- (3- fluoro-4- methylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine 4- (dimetyIami- no) benzaldehyde 2- (3-fluoro-4- methylphenyl) - ethenyl-boronic acid acid IR 3360, 31603000, 1660, 1590, 1555, 1340, 1200, 820; MS m / z 374 (M + H) &lt; ^{+ &gt};. 55 4-amino-6- (3- fluoro-4- methylphenyl) -7- (4- (Thiophen-2- yl) phenyl) pyrido [2, 3-d] pyrimidine 4- (thiophen-2- karoboxaldehyd) benzaldehyde 2- (3-fluoro-4- methylphenyl) - ethenyl-boronic acid acid IR 3600-3300, 3200, 3020, 1620, 1415; MS m / z 337 (M + H) &lt; ^{+ &gt};.

56 4-amino-6- (3- phenylpropyl) -7- (4- (Methoxyphenyl) phenyl l) -pyrido [2,3- d] pyrimidine 4-metoxybenz- aldehyde 5-phenyl-1-pentenylboronic acid NMR (CDC1 ₃₎ δ 8.70 (s, lH), 08.06 (s, IH), 7:53 (d, J = 9 Hz, 2H), 7.22 (m, 3H), 7.6 (d, J = 8 Hz, 2H), 6.94 (d, J = 9 Hz, 2H), 6.19 (s, br, 2H), 3.88 (s, 3H), 2.88 (m, 2H), 2.57 (m, 2H), 1.88 (m, 2H); MS m / z 371 (M + H) &lt; - &gt; 57 ' 4-amino-6- (3- phenylpropyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 5-phenyl-1-pentenylboronic acid , 1 1 NMR (CDCl3) δ 8.73 (s, 1H), 7.88 (s, 1H), 7.58 (d, J = 8Hz, 2H), 7.22 (m, 3H), 7.10 (d, J = 8Hz, 2H), 6.73 (d, J = 9 Hz, 2H), 5.78 (s, br, 2H), 3.04 (s, 6H), 296 (m, 2H), 2.61 (t, J = 8 Hz, 2H), 1.91 (m, 2H); MS m / z 384 (M + H) &lt; ^{+ &gt};. 58 4-Amino-6- (2-phenylethyl) -7- (4 (dimethylamino) phenyl) pyrido [2,3d] pyrimidine 4- (dimetylami- no) benzaldehyde 4-phenyl-l- butenyl boronic acid NMR (CDCl3) δ 8.75 (s, 1H), 7.69 (s, 1H), 7.65 (m, 2H), 7.21 (m, 2H), 704 (m, 2H), 6.79 (m, 2H), 5.57 ( s, br, 2H); 3.25 (m, 2H); 3.04 (s, 6H); 2.S5 (m, 2H); MS m / z 370 (M + H) &lt; ^{+ &gt};.

59 4-amino-6- (Phenylmethyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- pyrimidine 4- (dimetylami- no) benzaldehyde 3-phenyl-1-propenylboronic acid NMR (CDCl3) δ 8.74 (s, 1H), 7.74 (s, JH), 7.65 (d, J = 9 Hz, 2H), 7.30 (m, 3H), 7.10 (m, 2H), 6.74 (d, J = 9 Hz) (2H), 5.64 (s, br, 2H), 4.29 (s, 2H), 3.02 (s, 6H) ,; MS m / z 356 (M + H) &lt; ^{+ &gt};. 60 4-amino-6- (Cyclohexylmethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine 4- (dimetylami- no) benzaldehyde 1 3-Cyclohexyl-1-propenylboronic acid NMR (CDCl3) δ 8.75 (s, 1H), 7.90 (s, 1H), 7.59 (d, J = 9 Hz, 2H), 6.76 (d, J = 9 Hz, 2H), 5.82 (s, br, 2H); 3.03 (s, 6H); 2.83 (d, J = 7 Hz, 2H), 1.70-1.40 (m, 6H), 1.07 (m, 3H), 0.83 (m, 2H); MS m / z 362 (M + H) &lt; + &gt;. 61 4-amino-6-butyl 7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine 4- (dimetylami- no) -benzaldeliyd 3-Hexenylboronic acid NMR (CDCl ₃ ) δ 8.74 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 9 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 5.86 (s, 2H), 3.04 (s, 6H), 2.91 (m, 2H), 1.57 (m, 2H), 1.32 (sextet, J = 7 Hz, 2H), 0.87 (t, J = 7 Hz, 3H); MS m / z 322 (M + H) &lt; + &gt;

62 4-amino-6-pentyl- 7- (4- (Dimethylamino) phenyl) pyrido [2,3- pyrimidine 1 4- (dimetylami- no) benzaldehyde to 3-Heptenylboronic acid NMR (DMSO-d 6) δ 8.53 (s, 1H), 8.45 (s, 1H), 7.47 (d, J = 8 Hz, 2H), 6.82 (d, J = 8 Hz, 2H), 3.34 (s, 1H), 3.32 (s, 1H), 2.99 (s, 6H), 2.81 (m, 2H), 1.58 (m, 2H), 1.23 (m, 4H), 0.82 (m, 3H); MS m / z 336 (M + H) &lt; ^{+ &gt};. 63 '· 4-amino-6- (2- methylpropyl) pentyl 1-7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine l 4- (dimetylami- no) benzaldehyde F 4-Methyl-1 pentenylboronic acid NMR (CDC1 ₃₎ δ 8.76 (s, lH), 7.88 (s, IH), 7.61 (d, J = 9 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 5 76 (s, br, 2H 1.03 (s, 6H), 2.84 (d, J = 7 Hz, 2H), 1.78 (m, 1H), 0.78 (d, J = 6 Hz, 6H); MS m / z 322 (M + H) &lt; ^{+ &gt};. 64 4-amino-6-propyl 7- (4- (dimethyl- amino) phenyl) pyridine [2,3-d] pyrimidine 4- (dimetylami- no) benzaldehyde 1-Pentenylboronic acid NMR (DMSO-d 6) δ 8.52 (s, 1H), 8.45 (s, 1H), 7.90 (s, br, 2H), 748 (d, J = 8Hz, 2H), 6.82 (d, J = 8Hz, 2H), 2.99 (s, 6H), 28 (m, 2H), 1.60 (sextet, J = 7Hz, 2H), 0.85 (J = 7Hz, 3H); MS m / z 308 (M + H) &lt; ^{+ &gt};.

65 4-amino-6- (3- cyanopropyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- pyrimidine 4- (dimetylami- no) benzaldehyde 5-Cyano-1-pentenylboronic acid NMR (DMSO-d 6) δ 8.56 (s, 1H), 8.47 (s, 1H), 7.94 (s, br, 2H), 7.50 (d, J = 9 Hz, 2H), 6.83 (d, J = 9 Hz, 2H) 1.00 (s, 6H), 2.93 (m, 2H), 2.50 (m, 2H), 1.90 (m, 2H); MS m / z 333 (M + H) &lt; ^{+ &gt};. 66 4-amino-6- (3- riitrofenyl) -7- (4- (Dimethylamino) phenyl yl) pyrido [2,3- d] pyrimidine 4- (dimetylami- no) benzaldehyde 2- (3- nitrophenyl) ethenylboronic acid IR 3360, 3100, 1590, 1560; MS m / z 387 (M + H) &lt; ^{+ &gt};. 67 4-amino-6-pentyl- 7- (thiophen-2- yl) pyrido [2,3- pyrimidine thiophene-2- carboxaldehyde 1-Heptenylboronic acid 1 IR 3320, 3 100, 1560, 1430; MS m / z 299 (M + H) &lt; ^{+ &gt};.' 68 4-amino-6- (3- karboxamidopropy 1) 7- (4- (Dimethylamino) phenyl) pyrido [2,3- d] pyrimidine 4 (Dimethylamino) - benzaldehyde 5-Cyano-1-pentenylboronic acid IR 3325, 3120, 1660, 1595; MS m / z 351 (M + H) &lt; ^{+ &gt};. 69 4-amino-6 - ((4- methoxyphenyl) methyl ) -7- (thiophen-2-yl) -pyrido [2,3- Ipyrimidin thiophene-2- carboxaldehyde 2- (4- methoxyphenyl) propenylboronic acid IR 3360, 3100, 1605, 1565; MS m / z 349 (M + H) &lt; ^{+ &gt};. 70 4-amino-6 - ((3- bromophenyl) methyl) - 7- (thiophen-2- yl) pyrido [2,3d] pyrimidine thiophene-2- carboxaldehyde 2- (3-bromophenyl) propenylboronic acid IR 3440, 3120, 1605, 1565; MS m / z 397/399 (M + H) &lt; ^{+ &gt};. 71 4-amino-6 - ((4- (2- propyl) phenyl) methyl ) -7- (thiophen-2- yl) pyrido [2,3- d] pyrimidine thiophene-2- karboxaldeliyd 2- (4- (2-propyl) phenyl) propenylboronic acid IR 3440, 3080, 1600, 1560; MS m / z 361 (M + H) &lt; ^{+ &gt};.

72 4-amino-6 - ((4- methoxyphenyl) methyl ) -7- (4- (2- propyl) phenyl) pyridine [2,3-d] pyrimidine 4-isopropyl- benzaldehyde 2- (4- methoxyphenyl) propenylboronic acid IR 3360, 3120, 1565, 1510; MS m / z 385 (M + H) &lt; ^{+ &gt};. 73 4-amino-6 - ((4- bromophenyl) methyl) - 7- (thiophen-2- yl) pyrido [2,3- d] pyrimidine thiophene-2- carboxaldehyde 2- (4-Bromophenyl) propenylboronic acid IR 3440, 3160, 1625, 1560; MS m / z 397/399 (M + H) &lt; ^{+ &gt};. 74 4-amino-6 - ((3- phenyl) methyl) - 7- (thiophen-2- yl) pyrido [2,3- - dpyrimidine thiophene-2- carboxaldehyde 2- (4-fluorophenyl) propenylboronic acid IR 3320, 3160, 1600, 1560; MS m / z 337 (M + H) &lt; ^{+ &gt};. 75 '· 4-amino-6 - ((4- bromophenyl) methyl) - 7- (thiazol-2- yl) pyrido [2,3- pyrimidine thiazol-2- carboxaldehyde 2- (4-Bromophenyl) propenylboronic acid IR 3450, 3100, 1635, 1560; MS m / z 398/400 (M + H) &lt; ^{+ &gt};. 76 4-amino-6 - ((3- methoxyphenyl) methyl ) -7- (thiophen-2- yl) pyrido [2,3d] pyrimidine thiophene-2- carboxaldehyde 2- (3- methoxyphenyl) propenylboronic acid IR 3450, 3150, 1600, 1560; MS m / z 349 (M + H) &lt; ^{+ &gt};. 77 4-amino-6- (Phenylmethyl) -7- (Thiophen-2- yl) pyrido [2,3- d] pyrimidine thiophene-2- carboxaldehyde 2-Phenyl-1 propenylboronic acid IR 3390, 3110, 1605, 1565; MS m / z 319 (M + H) &lt; ^{+ &gt};. 78 4-amino-6 - ((3- metoxyfe- phenyl) methyl) -7- (4- (Dimethylamino) phenyl) pyrido [2,3- pyrimidine 4 (Dimethylamino) - benzaldehyde 2- (3- methoxyphenyl) propenylboronic acid IR 3310, 3080, 1600, 1565; MS m / z 386 (M + H) &lt; ^{+ &gt};. 79 4-amino-6- (4-methylphenyl) -7- (4 (trifluoromethyl) phenyl) pyrido [2, 3-d] pyrimidine 4- (trifluoromethyl) - benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3230, 1325, 820; MS m / z 381 (M + H) &lt; ^{+ &gt};. 80 4-amino-6- (4- methylphenyl) -7- (4- (Phenyl) -pyrido [2,3-d] pyrimidine 4-methyl- benzaldehyde 2- (4-inelylfenyl) - ethenyl-boronic acid acid IR 3450, 1449, 1340, 820; MS m / z 327 (M + H) ^4th

81 4-amino-6- (4- methylphenyl) -7- (4- methoxyphenyl) pyridine [2,3-d] pyrimidine 4-methoxy- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3375, 1600, 820; MS m / z 343 (M + H) &lt; ^{+ &gt};. 82 4-amino-6- (4- methylphenyl) -7- (4- ethylphenyl) pyrido [2 , 3-d] pyrimidine 4-ethyl - benzaldehyde. 2- (4-methylphenyl) - ethenyl-borónoýá acid IR 3340, 1558, 1340, 820; MS m / z 341 (M + H) &lt; ^{+ &gt};. 83 4-amino-6- (4- methylphenyl) -7- (4- cyanophenyl) pyrido [2,3-d] pyrimidine 4-cyano- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3320, 1560, 820; MS m / z 338 (M + H) &lt; ^{+ &gt};. 84 4-amino-6- (4- methylphenyl) -7- (4- ac'etamidofenyl) py pyrido [2,3- pyrimidine 4-acetamido- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3325, 1520, 820; MS m / z 370 (M + H) &lt; ^{+ &gt};. 85 4-amino-6- (4- methylphenyl) -7- (4- phenoxyphenyl) pyridine [2,3-d] pyrimidine 4-phenoxy benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3340, 1550, 1240, 750; MS m / z 405 (M + H) &lt; ^{+ &gt};. 86 4-amino-6- (4- methylphenyl) -7- (4- nitrophenyl) pyrido [ 2,3-d] pyrimidine 4-nitro- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3390, 1340, 850; MS m / z 358 (M + H) &lt; ^{+ &gt};. 87 4-Amino-6- (4-methylphenyl) -7- (4-fluorophenyl) pyrido [2,3-d] pyrimidine 4-fluoro- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3320, 1550, 1340, 840; MS m / z 3 31 (M + H) ⁺ . 88 4-Amino-6- (4-methylphenyl) -7- (4-chlorophenyl) pyrido [2,3-d] pyrimidine 4-chloro- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3340, 1550, 1340, 910; MS m / z 347 (M + H) ⁺ . 89 4-amino-6- (4- methylphenyl) -7- (4- aminophenyl) pyrido [2,3-d] pyrimidine 4-amino- benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3325, 1550, 820; MS m / z 328 (M + H) &lt; ^{+ &gt};. 90 4-amino-6- (4- methylphenyl) -7- (4- metyltiofe- phenyl) pyrido [2,3- pyrimidine 4-methylthio benzaldehyde 2- (4-methylphenyl) - ethenyl-boronic acid acid IR 3310, 1560, 1340, 819; MS m / z 359 (M + H) &lt; ^{+ &gt};.

91 4-amino-6- (4- methylphenyl) -7 - ((4- phenyl) phenyl) pyrido [ 2,3-d] pyrimidine 4-phenyl benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3345, 1560, 820; MS m / z 389 (M + H) ⁺ . 92 4-amino-6- (4- methylphenyl) -7 - ((4- phenylmethoxy) phenyl) -pyrido [2,3- d] pyrimidine 4-phenylmethoxy, - benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3400, 1340, 1245, 700; MS m / z 419 (M + H) + 93 4-Amino-6- (4-methylphenyl) -7 - ((4M, N-diethylamino) phenyl) pyrido [2,3-d] pyrimidine 4- (N, N- diethylamino) - benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3330, 1550, 1200, 819; MS m / z 384 (M + H) &lt; ^{+ &gt};. 94 4-amino-6- (4-methylphenyl) -7 - ((4-2-phenylethenyl) ⁿ Fe-yl) -pyrido [2,3-d] pyrimidine 4- (2- phenylethenyl) - benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3460, 1600, 1340, 690; MS m / z 415 (M + H) &lt; ^{+ &gt};. 95 4-Amino-6- (4-methylphenyl) -7- (4- (2-methyl-2-propoxy) phenyl) pyrido [2,3-d] pyrimidine 4- (2-methyl-2- propoxy) - benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3315, 1550, 1160, 900; MS m / z 385 (M + H) &lt; ^{+ &gt};. 96 4-amino-6- (4- methylphenyl) -7- (3- chloro-phenyl) -pyrido [2 , 3-d] pyrimidine 4-clilór- benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3050, 1555, 1340, 825; MS m / z 347 (M + H) &lt; ^{+ &gt};. 97 4-Amino-6- (4-methylphenyl) -7- (3,5-dimethoxyphenyl) pyrido [2,3d] pyrimidine 3,5-dimethoxy- benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3430, 1600, 1200, 720; MS m / z 373 (M + H) &lt; ⁺ &gt; ^. 98 4-amino-6- (thiophen 2-yl |) -7- (4-MW- dimethyl phenyl) pyrido [2,3- d] pyrimidine 4- (O- diethylamino) - benzaldehyde 2- (thiophen-2-yl) - ethenyl-boronic acid acid IR 3320 1590 700 ,; MS m / z 348 (M + H +) 99 4-amino-6- (4- methylphenyl) -7- (Benzofuran-2- yl) pyrido [2,3- d] pyrimidine benznfurán 2- carboxaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid IR 3310, 1640, 750; MS m / z 353 (M + H) ^4th

100 4-Amino-6- (thiophen-2-yl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine thiophen-2-yl- carboxaldehyde 2- (thiophen-2-yl) - ethenyl-boronic acid acid IR 3315, 1560, 1420, 700; MS m / z 31 (M + H) &lt; ⁺ &gt; ^. ΙΟΙ 4-Amino-6- (thiophen-2-yl) -7- (4-methoxyphenyl) pyrido [2,3-d] pyrimidine 4-metoxybenz- aldeliyd 2- (thiophen-2-yl) - ethenyl-boronic acid acid IR 3400, 1560, 1250, 835; MS m / z 335 (M + H) &lt; ⁺ &gt; ^. 102 4-amino-6- (4- bromophenyl) -7- (4- ΛζΛ / '- dimetylfe- phenyl) pyridoÍ2,3- pyrimidine 4- (N, N- dimethylamino) - benzaldehyde 2- (4-bromophenyl) - ethenyl-boronic acid acid IR 3330, 1545, 1190, 810; MS m / z 420 (M + H) &lt; ^{+ &gt};. 103 4-Amino-6- (3'-bromo-4-methoxyphenyl) -7- (4-dimethylphenyl) pyrido [2,3-d] pyrimidine 4- (N, N- dimethylamino) - benzaldehyde 2- (3-bromo-4- methoxy-phenyl) - ethenyl-boronic acid acid IR 3380, 1590, 1200, 820; MS m / z 451 (M + H) &lt; ^{+ &gt};. 104 4-amino-6- (3-bromo-4-methoxyphenyl) -7 - ((thiophen-2-yl) pyrido [2,3d] pyrimidine) thiophen-2- carboxaldehyde 2- (3-Bromo-4-methoxyphenyl) ethenylboronic acid IR 3400, 1550, 1280, 715; MS m / z 414 (M + H) &lt; ^{+ &gt};. 105 4-amino-6- (4- methylphenyl) -7- (4- butoxy-phenyl) -pyrido [ 2,3-d] pyrimidine 4-butoxybenz- aldehyde 2- (4- methylphenyl) - ethenyl-boronic acid on the 106 4-amino-6- (4- methylphenyl) -7- (3- methoxyphenyl) -pyrido [2,3-d] pyrimidine 4-metoxybenz- aldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid on the 107 4-Amino-6- (4-methylphenyl) -7- (3,5-dichlorophenyl) pyrido [2,3-d] pyrimidine 3,5-diclilór- benzaldehyde 2- (4- methylphenyl) - ethenyl-boronic acid acid on the

Tť f MC-

Claims (18)

PATENT CLAIMS 1. A compound and its pharmaceutically acceptable salts and amides having the general formula ' d) wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom; . , R 1 and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group, and the dotted line indicates an optional double bond. A compound according to claim 1, wherein R ³ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic, and R ⁴ is selected from the group consisting of aryl, arylalkyl, heteroaryl or heterocyclic group. The compound of claim 1, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen, lower alkyl, arylC 1 -C ₆ alkyl, -C (O) C 1 -C 6 alkyl, -C (O) aryl, C (O) heterocyclic, or may be linked to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to two additional heteroatoms selected from O, N or S; R ³ and R ⁴ are independently selected from the group consisting of: C 1 -C 6 alkyl, C 2 Cealkenylu, C 2 -C 6 alkynyl, C ₃ -Cgcykloalkylu, heteroaryl or substituted-heteroaryl Cealkylu-Cealkylu, aryl-Co-C ₆ -alkyl, or substituted aryl-Cealkylu, heteroarylC2 6 alkenyl or substituted _{heteroarylC2-C6} alkenyl, arylC2-CcalkenyIu or substituted arylC2-C6 alkenyl, heteroarylC2 -C 6 alkynyl, or substituted heteroarylC2-Cealkynylu, arylC ₂ -Cealkynylu or substituted arylC2-Cealkynylu, wherein the substituents of aryl or heteroaryl, 1-4 are independently selected from the group consisting of halogen, cyanoC Cealkylu, heteroaryl, heterocyclic, C Cealkyloxy _t, C-CealkyloxyCi Cealkylu , arylC 1 -C 6 alkyl, H 2 CN-C 1 -C 6 alkyl, arylC 1 -C 6 alkyloxy, H 2 NC (O), cyano, C 2 -C ₆ alkenyl, C 2 -C ₆ alkynyl, C 1 -C ₆ alkyl, C 2 -C 6 alkenyldialkylmalonyl, CF ₃ , -OH, C 1 -C 6alkyloxyC 1 -C 6 alkykyloxy, SOnC 1 -C 6 alkyl, wherein n is 1-3, C 1 -C 6 alkylthio, C 1 -C 6 alkylacryl, CF ₃ O, CF ₃ , C 1 -C ₄ alkylenedioxy, C 1 -C ₆ alkylene acrylic, H 2 N (CO) NH, N-formyl (heterocyclic ), NO 2, NR ⁵ R CoCcalkylu ^6, wherein the substituents R ⁵ and R ⁶ are independently selected from hydrogen, Ci-6 alkyl, HC (O), C | -CealkyloxyC | -Cealkvl C | -Cealkyloxy, CiC6alkylC (O) CF 3 C (O), NR ⁷ R ⁸ C 1 -C ₆ alkylC (O), phthalinidoC, -C ₆ C (O), CNC, -C ₆ alkyl, H ₃ NC (O) NH-, heteroaryl, NR ⁷ R 8 ^with C 1 -C 6 alkylC (O ), C 1 -C 6 alkyloxycarbamidoC 1 -C 6 alkyl, wherein R ⁷ and R ⁸ are independently selected from these variables for R ⁵ and R ^6, or R ⁵ and R ^6, or R ⁷ and R 8 may be joined together with a nitrogen atom to which they are attached to form a five to seven membered ring and optionally containing one to three additional heteroatoms selected from O, N or S, wherein the substituents are selected from C 1 -C ₆ alkyl. 4. The compound according to claim 1, characterized in that the radicals R ⁴ and R @ ^J are 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; 2- (N-methylamino) -5-pyrimidinyl; 2- (1 morpholinyl) -5-pyrimidinyl; 2- (I-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- (dimetylamiTio) 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-4pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4- (acetylamino) phenyl; 4- (dimethylamino) -3-fluorophenyl; 41 _t (dimethylamino) phenyl; 4- (imidazol-l-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-formyl amino) 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-amino) -phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophen-2-yl) phenyl; 4- (ureido) phenyl; 4- (2- (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetyl aminoethyl) 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; 4diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 457 fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl; 4-metyIaminofenyl; 4-methylsulfonylphenyl; 4morpholinylphenyl; 4-N- (2- (dimethylamino) ethyl) -N-formylamino) phenyl; 4-N- (3-methoxypropionyl) -N-isopropylamino) phenyl; 4-N-ethyl-N- (2-metoxye'tyl) amino) phenyl; 4-N-formyl-piperidinylphenyl; 4-nitrophenyl; 4-piperidinyl phenyl; 4-pyridylphenyl; 4pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5 (dimethylamino) thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3-dimetylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinyl phenyl; 6- (N-methyl-N-formylamino) -3-pyridinyl; 6- (N-methyl-N (2-methoxyethyl) amino) -3-pyridinyl; 6- (2-oxo-oxazolidinyl) -3-pyridinyl; 6dimetylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3'pyridinyl;6-pyrrolidinyl-3-pyridinyl; (2-propyl) -3-pyridines and (4formylamino) phenyl; (Thiophen-2-yl) methyl; (thiophen-3-yl) methyl, butyl; cycloheptyl; pentyl; thiophen-2-yl; l- (3-bromophenyl) ethyl; 2- (Nfenylmetoxykarbonyl) aminophenyl; 2- (3-bromo-phenyl) ethyl; 2- (3-cyanophenyl) methyl; 2- (4-bromophenyl) ethyl; 2- (5-chloro-2- (thiophen-3-yl) phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3- (furan-2) 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-diethylmalonylalylphenyl; 3-dimethylaminophenyl; 3-ethoxyphenyl; -trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl, 3-iodophenyl; 3-methoxyethyoxyphenyl, 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3- t -butylacrylphenyl; 3-trifluoromethoxyoxyphenyl; 3-trifluoromethylphenyl, 3-vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di (trifluoromethyl) phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethoxyphenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bromo-thiophen-2-yl; 4-butoxy-phenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromo-thiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5 phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; and (5-chloro-2- (358 chlorophenyl) methyl; (2-bromophenyl) methyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl. A compound according to claim 1 of the formula wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring, optionally containing an additional oxygen or nitrogen atom; the substituents R ³ and R ⁴ are independently selected from lower-al and ^one alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or heterocyclic group. The compound of claim 5, wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R ⁴ is aryl, arylalkyl, heteroaryl or heterocyclic. The compound of claim 5, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen, lower alkyl, arylC 1 -C 6 alkyl, -C (O) C 1 -C 6 alkyl, -C (O) aryl, C (O) ) a heterocyclic group or may be linked to the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing one to two additional heteroatoms selected from O, N or S; R ³ and R ⁴ are independently selected from the group consisting of: C 1 -C ₆ alkyl, C 2 -alkenyl, C 2 -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, lieteroarylC ₀ -C ₆ alkyl or substituted heteroarylC ₁ -C ₆ alkyl, arylC ₀ -C ₆ alkyl or substituted arylC ₀ -C ₆ alkyl, heteroaryl C ₂ -C ₆ alkenyl or substituted heteroaryl C ₂ -C ₆ alkenyl, arylC ₂ -C ₆ alkenyl or substituted arylC ₁ -C ₅ alkenyl; C ₆ alkynyl, arylC 2 -C ₆ alkynyl or substituted arylC 2 -C ₆ alkynyl wherein the substituents 1-4 of heteroaryl or aryl are independently selected from the group consisting of halogen, oxo, cyanoC 1 -C 6 alkyl, heteroarylC 0 -C 6 alkyl, heterocyclic C 0 -C 6 alkyl, C 1 -C 6 alkyloxy C 1 -C ₆ alkyloxy, arylC 1 -C ₆ alkyl, arylC 1 -C ₆ alkyloxy, R ⁵ R ⁶ NC (O), cyano, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C ₆ alkyl, C 2 -C ₆ alkenyldialkylmalonyl, CF 3, OH, C 1 -C 6 alkyloxyC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxy, C 1 -C 6 alkyloxy, wherein n is 1-2, C 1 -C 6 alkylthio, C 1 -C 6, alkyl acrylate, CF 3 O, CF 3, C 1 -C 4 alkylenedioxy, C 1 -C 6 alkylaryl, R ⁵ R ⁶ N (CO) NR ⁵ , N-formyl (heterocycle NO 2, NR ⁵ R ⁶ CoC ₆ alkyl, wherein R ⁵ and R ⁶ are independently selected from hydrogen, C 1 -C 6 alkyl, HC (O), C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylC (O), CFjC (O) NR ⁷ R ⁸ C -C6alkylC (O), ftalimidoC, C, _and C (O), C, CôalkylSOn, wherein n is l and 2, CNCi-COalkyl, R ⁷ R ^S NC (O) NR ⁷ -, heteroaryl, NR ⁷ R ⁸ C ¹ -C 6 alkylC (O), C 1 -C 6 alkyloxycarbamidoC 1 -C 6 alkyl, wherein R and R are independently selected from those defined for R ⁵ and R ⁶ or the substituents R ^5, and R ^d or the substituents R ⁷ and R ^s may be taken together with the nitrogen to which they are attached to form a five to seven membered ring and optionally containing one to three additional heteroatoms selected from O, N, or S, wherein the substituents are selected from C 1 -C 6 alkyl. The compound of claim 5, wherein R ³ and R ⁴ are independently selected from phenyl; thiophen-2-yl, 1-methyl-2-oxobenzoxazolin-5-yl; 2- (dimethylamino) -5-pyrimidinyl; 2- (N-formyl-N-methylamino) -3-pyrimidinyl; . 2- (N- (2-methoxyethyl) -N-methylamino) -5-pyrimidinyl; 2- (N-methylamino) 5-pyrimidinyl; 2- (lmorfolinyI) -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-methoxy-phenyl; 3-bromo-4- (dimethylamino) phenyl; 3-methoxyphenyl; 3-methyl-4- (N-acetyl-N-methylamino) phenyl; 3-methyl-4 (N-formyl-N-methylamino) phenyl; 3-methyl-4- (N-methyl-N- (trifluoroacetyl) amino) phenyl; 3-methyl-4- (N-methylamino) phenyl; 3-methyl-4-pyrrolidinylphenyl, 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4 (acetylamino) phenyl; 4- (dimethylamino) -3-fluorophenyl; 4- (dimethylamino) phenyl; 4- (imidazol-1-yl) phenyl, 4- (methylthio) phenyl; 4- (morpholinyl) phenyl; 4- (N- (2 (dimethylamino) ethyl) amino) phenyl; 4- (N- (2-methoxyethyl) amino) phenyl; . 4- (N-acetyl-N-methylamino) phenyl; 4- (N-ethyl-N-formylamino) phenyl; 4- (N-ethylamino) phenyl; 4- (N-formyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-isopropylamino) phenyl; 4- (N-methyl-N - ((2-dimethylamino) ethyl) amino) phenyl; 4- (N-methyl-N- (2- (N-phthalimidyl) acetyl) amino) phenyl; 4- (N-methyl-N- (2-cyano) ethylamino) phenyl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-methyl-N- (3-methoxy) propionylamino) phenyl; 4- (N-methyl-N-acetylamino) phenyl; 4- (N-methyl-Nformylamino) phenyl; 4- (N-methyl-N-amino) -phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophen-2-yl) phenyl; 4- (ureido) phenyl; 4- (2- (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetylamino) amino) phenyl; 4- (2-inetoxy) 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-butoxy-phenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyano phenyl; 4diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl, 4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropyl-phenyl; 4-methoxyphenyl; 4-methylaminophenyl; 4-methylsulfonylphenyl; 4morpholinylphenyl; 4-N- (2- (dimethylamino) ethyl) -Nformylamino) phenyl; 4-N- (3-methoxypropionyl) -N-isopropylamino) phenyl; 461 N-ethyl-N- (2-methoxyethyl) amino) phenyl; 4-N-fornylpiperidinylfenyl; 4-nitro; 4piperidinylphenyl; 4-pyridylphenyl; 4pyrrolidinylphenyl; 4-tbutylakrylfenyl; 5- (dimethylamino) thiophen-2-yl; 5-amino-2-pyridyl; 5dimetylamino-2-pyrazinyl; 3-dimetylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6- (N-methyl-N-formylamino) -3-pyridinyl; 6r (N-Methyl-N- (2-methoxyethyl) amino) -3-pyridinyl; 6- (2-oxo-oxazolidinyl) -3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6morfolinyl-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; l- (3-bromophenyl) ethyl; 2- (N-phenylmethoxycarbonyl) aminophenyl; 2- (3-bromophenyl) ethyl; 2- (3-cyanophenyl) methyl; 2- (4-bromophenyl) ethyl; 2- (5-chloro-2- (thiophen-3-yl) phenyl; 2-bromophenyl, 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3- (furan-2-yl) phenyl; 3- (thiophen-2-yl) phenyl; 3- (2-pyridyl) phenyl; 3- (3-methoxybenzyl) phenyl; 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; 3diethylmalonylalylphenyl; 3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3- t -butylacrylphenyl; 3-trifluoromethoxyphenyl; 3- trifluoromethylphenyl; 3-vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl; 3,5-di (trifluoromethyl) phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethyl-phenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bľómtiofen-2-yl; 4-butoxy-phenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl, 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromo-thiophen-2-yl; 5cyklohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl) methyl, (2-bromophenyl) methyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl. The compound of claim 5, wherein R ³ and R ^J are independently selected from the group consisting of: phenyl; 4-dimethylaminophenyl; 4-methylphenyl; 4-bromophenyl; 4-pyridinyl; (5pyrimidinyl) phenyl; 2- (2-pyridinyl) ethenyl) phenyl; 3-pyridinyl; thiophen-3-yl; 2-pyridyl; 3,4-methylenedioxyphenyl; butyl; 5-bromo-thiophen-2-yl; 5-yl methylthiophene2; 4- (trifluoromethoxy) phenyl; 3-phenoxyphenyl; 5-nitro-thiophen-2-yl; 4brómtiofen-2-yl; 3-metyltiofpn-2-yl; furan.-2-yl; furan-3-yl; 5-methyl-furan-2-yl; 4- (2-propyl) phenyl; 3,4-dimethoxyphenyl; hexyl; 2-methyl-2-propyl; 4- (2-propyl) phenyl; 4-propylphenyl; 3-methoxyphenyl; 3-bromophenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 3-chlorophenyl; 3,5-dichlorophenyl; 3-carboxyphenyl, 3- (2-propyl) phenyl; 4- (2-methyl-2-propyl) phenyl; 4-fluorophenyl; 4-methoxyphenyl; 3- (phenylmethoxy) phenyl; 4-chlorophenyl; 3-fluoro-4-methylphenyl; 3-phenylpropyl; 4-methoxyphenyl; 3-phenylpropyl; 2-phenylethyl; phenylmethyl; cyclohexylmethyl; -.- pentyl; 2-methylpropyl; propyl; 3-cyanopropyl; 3-nitrophenyl; 3-carboxamidopropyl; (4-methoxyphenyl) methyl; (3-bromophenyl) methyl; (4- (2-propyl) phenyl) methyl); (4-methoxyphenyl) methyl); (4-bromophenyl) methyl); (3-fluorophenyl) methyl; (4-bromophenyl) methyl; thiazol-2-yl; (J-methoxyphenyl) methyl; phenylmethyl; (3-methoxyphenyl) methyl, 4-methylphenyl; 4- (trifluoromethyl) phenyl; 4-etyIfenyl; 4-acetamidophenyl; 4-phenoxyphenyl; 4-nitrophenyl; 4-fluorophenyl; 4-chlorophenyl; 4-aminophenyl; 4-methylthiophenyl; (4-phenyl) phenyl; (4-phenylmethoxy) phenyl; (4-N, Ndietylamino) phenyl; (4-2-phenylethenyl) phenyl; (2-methyl-2-propoxy) phenyl, 3-chlorophenyl; 3,5-dimethoxyphenyl; 4-N, N-dimethylphenyl; benzofuran-2-yl; 3-bromo-4-methoxyphenyl; 4-butoxy-phenyl; 3-methoxyphenyl and 3,5-dichlorophenyl. 10. The compound of Claim 5 that is; 4-amino-6-phenyl-7- (4-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (dimethylamino) phenyl) -7- (4- (dimethylamino) phenyl) pyrimido [2,3djpyrimidin; 4-amino-6- (4-methylphenyl) -7-phenyl-pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-bromophenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (4- (dimethylamino) phenyl) -7- (4-pyridinyl) pyrido [2,3-d] pyrimidine; 4-Amino-6- (4- (dimethylamino) phenyl) -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine: 4-amino-6- (4-methylphenyl) -7- (4- (5-pyrimidinyl) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (2- (2-pyridinyl) ethenyl) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-pyridinyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (thiophen-3-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (2-pyridinyl) pyrido [Z, 3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3,4-methylenedioxyphenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6-butyl-7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; _/ 4-amino-6-butyl-7- (thiophen-3-yl) -pyrido ^[2,3, d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-bromo-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-methyl-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (trifluoromethoxy) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-ferioxyfenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-bromo-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-methyl-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (furan-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-metyIfenyI) -7- (furan-3-yl) pyrido (2,3-d] pyrimidin; 4-amino-6- (4-metyIfenyI) -7- (5-methyl-furan-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (2-propyl) phenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (2-propyl) phenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine, 4-amino-6- (4-methylphenyl) -7- (5-nitro-thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (dimethylamino) phenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3,4-dimethoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (3,4-dimethoxyphenyl) -7- (5-nitrothiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-Avino-6-hexyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6-hexyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (2-methyl-2-propyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; I 4-amino-6- (4-propylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3,4-dimethoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine, 4-amino-6- (3-methoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-bromophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-fluorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-trifluoromethylphenyl) -7- (4- (dimethylamino) phenyl) pyľido [2,3-d] pyrimidine; 4-amino-6- (3-chlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3,5-dichlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3,4-methylenedioxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine; 4-Amino-6- (3,4-methylenedioxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-methoxycarbonylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4- (2-methyl-2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-fluorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methoxyphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3- (phenylmethoxy) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3djpyrimidín; 4-amino-6- (4-chlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-fluoro-4-methylphenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (3-fluoro-4-methylphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (3-phenylpropyl) -7- (4-methoxyphenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (3-phenylpropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (2-phenylethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (phenylmethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (cyclohexylmethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; I 4-amino-6-butyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6-pentyl · 7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (2-methylpropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6-propyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-cyanopropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-nitrophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6-pentyl-7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (3-carboxamidopropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine; 4-amino-6 - ((4-methoxyphenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6 - ((3-bromophenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6 - ((4- (2-propyl) phenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6 - ((4-methoxyphenyl) methyl) -7- (4- (2-propyl) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6 - ((4-bromophenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6 - ((3-fluorophenyl) methyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6 - ((4-bromophenyl) methyl) -7- (thiazol-2-yl) -pyrido [2,3-d] pyrimidine; 4-Amino-6 - ((3-methoxyphenyl) methyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (phenylmethyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6 - ((3-methoxyphenyl) methyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (trifluoromethyl) phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methyl-phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methoxyphenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-ethyl-phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-cyanophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-acetamidophenyl) pyrido [2,3-d] pyrimidine; »· I 4-amino-6- (4-methylphenyl) -7- (4-phenoxy-phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-nitrophenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-fluorophenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-chloro-phenyl) -pyrido [2,3-d] pyrimidine; 4-Amino-6- (4-methylphenyl) -7- (4-aminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methylthiophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7 - ((4-phenyl) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7 - ((4-phenylmethoxy) phenyl) pyrido [2,3-d] pyrimidine; 4-Amino-6- (4-methylphenyl) -7 - ((4-N, N-dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-Amino-6- (4-methylphenyl) -7 - ((4-2-phenyletenyl) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (2-methyl-2-propoxy) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-chlorophenyl) pyrido [2,3-d] pyrimidine; 4-Amino-6- (4-methylphenyl) -7- (3,5-dimethoxyphenyl) pyrido [2,3-d] pyrimidine; modified page 4-amino-6- (thiophen-2-yl) -7- (4-N, N-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (benzofuran-2-yl) -pyrido [2,3-d] pyrimidine; I t * 4-amino-6- (thiophen-2-yl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (thiophen-2-yl) -7- (4-methoxyphenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-Bromo-phenyl) -7- (4-N, N-dimethylaminophenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (3-bromo-4-methoxyphenyl) -7- (4-N, N-dimethylaminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-bromo-4-methoxyphenyl) -7- (thiophen-2-yl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-butoxy-phenyl) -pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-methoxyphenyl) -pyrido [2,3-d] pyrimidine; and 4-amino-6- (4-methylphenyl) -7- (3,5-dichlorophenyl) pyrido [2,3-d] pyrimidine. Use of a compound according to claim 1 or 5 for the preparation of a medicament for inhibiting adenosine kinase in a mammal. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or claim 5 in combination with a pharmaceutically acceptable carrier. Use of a compound according to claim 1 or 3 for the preparation of a medicament for the treatment of ischemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal dysfunction, diabetes and blood infection in mammals Use according to claim 13, characterized in that said medicament is suitable for the treatment of at least one of pathological conditions selected from cerebral ischemia, myocardial ischemia, angina, coronary artery graft bypass surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions , epilepsy, anxiety, schizophrenia, painful perception, neuropathic pain, visceral pain, arthritis, infection, diabetes, and abnormal gastrointestinal motility. A process for preparing a compound having the formula wherein R ¹ and R ² are hydrogen, R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic or substituted versions thereof; R ⁴ is aryl, heteroaryl or heterocyclic or substituted versions thereof; characterized by comprising I (a) reaction of 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the general formula: (HO) _2B ^^ _R3 wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl or heteroaryl or heterocyclic or substituted versions thereof, in the presence of tetrakistriphenylphosphine palladium (O) and an aqueous alkali metal base, and isolating a first of an intermediate having a general pattern. R ³ (b) reacting the first intermediate with an aldehyde compound having the formula R ⁴ -CHO, wherein R ⁴ is aryl, heteroaryl or heterocyclic or substituted versions thereof, under anhydrous conditions and with removal of water from the reaction, and isolating the compound of formula (II). . A process for the preparation of a compound having the general formula wherein R ¹ and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom, with the requirement that both R ¹ and R ² are not hydrogen; ^One R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or heterocyclic or substituted versions thereof; R ⁴ is aryl, heteroaryl or heterocyclic or substituted versions thereof; characterized by comprising (a) reacting a compound having the formula wherein R ¹ and R ² are hydrogen; R ^- is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl, or heterocyclic or substituted versions thereof; R ⁴ is aryl, heteroaryl or heterocyclic or substituted versions thereof; with a compound selected from the group consisting of (i) an alkylating agent of the general formula R'-Y wherein R ¹ - is lower alkyl and Y is selected from the group consisting of halide, methanesulfonate and p-toluenesulfonate; (ii) an arylalkylating agent of formula R ¹ -lower alkyl-Y, wherein R ¹ is arylalkyl and Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate; (iii) acyl compounds of the general formula R * -Z, wherein R ¹ is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and (b) optionally, if desired that R ^{2 is} not hydrogen, reacting the compound of step (a) with a compound selected from the group consisting of (i) an alkylating agent of formula R ² -Y, wherein: ^R2 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent of formula R ² -lower alkyl-Y, wherein R ² is arylalkyl and Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate; (iii) acyl compounds of the formula R ² -Z, wherein R ² is an acyl group and Z is selected from the group consisting of an acid anhydride, halide or acyl activating group; and isolating the compound of formula (II) A process for preparing a compound having the general formula R ³ R ⁴ wherein R 1 and R ² are independently hydrogen, lower alkyl, arylalkyl or acyl, or may be joined together with the nitrogen atom to which they are attached to form a five to seven membered ring optionally containing an additional oxygen or nitrogen atom with the proviso that both R ¹ and R ² are not hydrogen; R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group or substituted versions thereof; R ⁴ is aryl, heteroaryl or heterocyclic or substituted versions thereof; characterized in that it comprises (a) reacting 6-amino-4-chloro-5-iodopyrimidine with a derivative of etenylborónovej having the formula (HO) ₂ B ^ \ _{R 3} wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl , aryl, arylalkyl, heterocyclic group or heteroaryl or substituted versions thereof, in the presence of tetrakistriphenylphosphine palladium (0) and an alkali metal aqueous base, and isolating the first intermediate having the general formula R ³ (b) reacting the first intermediate with an aldehyde of a compound having the formula R ⁴ -CHO wherein R ⁴ is aryl, heteroaryl or heterocyclic or substituted versions thereof, under anhydrous conditions; and R ³ And (c) reacting the fourth intermediate with an amine compound having the general formula R 1 -NH-R ² , wherein R ¹ and R ² are as follows, R ⁴ with removal of water from the reaction, and isolation of a second intermediate having the general formula; as described above, and isolating the compound of formula (II). 18. A compound of the formula; R ³ • R ⁴ wherein sign X is selected from the group consisting of a halogen or -OH and R ³ and R ⁴ are as defined above.