CZ360199A3 - Compounds of 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine - Google Patents

Abstract

A compound having the general formula (I), in the substituents R 1, R 2 2, R 3 and R 4 are defined variables, won from groups, such as are specified herein which include alkyl, atyl, heteroaryl and a heterocyclic group and a substituted version thereof, a process inhibition of adenosine kinase by application of these compounds, pharmaceutical which contains a therapeutically effective amount of these compounds in combination with a pharmaceutically acceptable carrier, method (investigation of cerebral ischemia, epileage, nociperption, pain, inflammation and sepsis in a mammal in need of such treatment, comprising administering a therapeutically effective amount of the compounds of the invention of the present invention, mammals and methods of making the same compounds.

Description

Technical field

The present invention relates to a method for inhibiting adenosine kinase by administering 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine compounds, pharmaceutical compositions containing such compounds, as well as novel 6,7-disubstituted-4aminopyrido [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 the phosphorylation of adenosine on AMP, preferably using ATP as a source of phosphate. Adenosine kinase has 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 every human tissue analyzed including kidney, liver, brain, spleen, placenta and pancreas. Adenosine kinase is a key enzyme in regulating 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 activation of specific ectocellular receptors, expertly designated P 1 receptors (Bumstock, in 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; 439445). Adenosine can play a role in a variety of central nervous system disorders such as schizophrenia, anxiety, depression and Parkinson's disease (Williams, M., in Psychopharmacology: The Fourth Generation of Progress, Bloom, Kupfer (eds.), Raven Press, New York) 1995, 643-655).

• · · · · · · · · · · · ·

Adenosine has also been implicated in modulating transmission in spinal cord pain pathways (Sawynok, et al., Br. J. 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). AK inhibitor has been found to reduce paw swelling in an adjuvant arthritis model in rats (Firestein, et al., Arthritis and Rheumatism, 1993, 36, S48).

Adenosine also exhibits various effects on the cardiovascular system including vasodilatation, atrioventricular conduction damage, and endogenous cardiac protection in myocardial ischemia and reperfusion (Mullane and Williams, Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, 289-334) ). 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, via the activation of its A1 receptors on adypocytes, has a role in diabetes (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 sepsis. While adenosine is commonly present at low levels in the extracellular space, its release is locally enhanced at the site (s) of excess cellular activity, in trauma or metabolic stress.

Secondly, in the extracellular space, adenosine activates specific extracellular receptors to develop various reactions that lead to normalization of cellular functions. (Bruns, Nucleosides Nucleotides, 7991, 10: 931-943; Miller and Hsu, J. Neurotranma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806) and its endogenous effects are therefore highly localized.

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

Pharmacological compounds directed to inhibit adenosine kinase provide potentially effective new therapies for disorders supported by potentiation of adenosine specific site and case specificities. Disorders where such compounds may be useful include conditions of ischemia such as cerebral ischemia, myocardial ischemia, angina, coronary bypass surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other thrombotic and embolic states, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal dysfunction such 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., J. Biol. Chem. 1979, 254: 2339-2345),

5-iodotubercidine (Wotring and Townsend, Cancer Res. 1979, 39: 3018-3023) and 5'-deoxy-5-iodotobercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347-355).

Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345) including 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 an 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., Europ. J. Cancer, 1981, 17: 43-51). Decreased cellular levels of adenosine kinase have also been associated with resistance to the toxic effects of 2'-deoxyadenosine (Hershfield and Kredich, Proc. Natl.

Acad. Sci. USA, 1980, 77: 4292-4296). The accumulation of deoxyadenosine triphosphate (dATP), derived from phosphorylation of 2'-deoxyadenosine, has been suggested as a toxic mechanism in immune deficiency associated with hereditary adenosine deaminase deficiency (Kredich and Hershfield, in The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., Eds. , McGraw-Hill, New York, 1045-1075).

B.S. Hurlbert et al. (J. Med. Chem., 11: 711-717 (1968)) disclose various compounds

2,4-diaminopyrido [2,3-d] pyrimidine having use as an antibacterial agent. R. K. Robins et al. (J. Amer. Chem. Soc., 80: 3449-3457 (1958)) disclose methods 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 folic acid. R. Sharma et al. (Indian J. Chem., 31B: 719-720 (1992)) disclose 4-amino-5- (4-chlorophenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pyrimidine and 4-amino-5- ( 4-methoxyphenyl) -7- (4-nitrophenyl) pyrido [2,3-d] pyrimidine having antibacterial activity. A. Gupta et al., J. Indian Chem. Soc., 71: 635-636 (1994)).

disclose compounds of 4-amino-5- (4-fluorophenyl) -7- (4-fluorophenyl) pyrido [2,3-d] pyrimidine and 4 amino-5- (4-chlorophenyl) -7- (4-fluorophenyl) pyrido [ 2,3-d] pyrimidine having antibacterial effects. L. Prakash et al., Pharmazie, 48, 221-222 (1993) disclose compounds of 4-amino-5-phenyl-7- (4-aminophenyl) pyrido [2,3-d] pyrimidine, 4-amino-5-phenyl -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine, 4-amino-5- (4-methoxyphenyl) -7- (4-aminophenyl) pyrido [2,3-d] pyrimidine and 4-amino-5- ( 4-methoxyphenyl) -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine having antifungal activity. P. Victory et al., Tetrahedron, 51: 10253-10258 (1995)) disclose the synthesis of 4-amino-5,7-diphenylpyrido [2,3-d] pyrimidine compounds from acyclic precursors. Bridges et al. (PCT Patent Application No. WO 95/19774 published on 27.07.1995) discloses various bicyclic heteroaromatic compounds as having utility for inhibiting epidermal growth factor tyrosine kinase.

SUMMARY OF THE INVENTION

The present invention provides 6,7-disubstituted-4-aminopyrido [2,3-d] pyrimidine compounds that are useful as adenosine kinase inhibitors.

In this aspect, the present invention provides novel compounds having the general formula (I)

(I) 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 further 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 contemplates 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 administering 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 (I) 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 above compound of formula (I) 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 sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (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, epilepsy, anxiety, perception, schizophrenia, nocturnal, schizophrenia , neuropathic pain, visceral pain, arthritis, sepsis, diabetes, and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) of the present invention.

The present invention also contemplates the pharmaceutically acceptable salts and amides of the compounds of formula (I), their use for inhibiting adenosine kinase in pharmaceutical compositions and for administration to a mammal.

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

(Π) 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 atom or nitrogen;

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

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

(Π) wherein R and R are hydrogen;

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

R ⁴ is aryl, heteroaryl or heterocyclic; which process comprises (a) reacting 4,6-diamino-5-iodopyrimidine ethenylboronové acid derivative having the general formula (HO) ₂ B ^ \ _{R 3} wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl , a heterocyclic or heteroaryl or substituted version thereof, in the presence of tetrakistriphenylphosphine palladium and an aqueous base of alkali metals, and isolating 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 removing water from the reaction, and isolating the compound of formula (II).

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

Cl

(Π) in which

R 7 and R 7 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 and R can not be hydrogen;

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

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

wherein R ¹ and R ² are hydrogen;

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

R ⁴ is aryl, heteroaryl or heterocyclic;

with a compound selected from the group consisting of

(i) an alkylating agent of formula R 1 -Y, wherein R ¹ is lower alkyl and Y is selected from the group consisting of halide, methanesulfonate, and toluenesulfonate;

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

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

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

(ii) an alkylating agent of formula R-lower alkyl-Y, wherein R ² is arylalkyl and the designation Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate;

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

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

(Π), wherein R and R 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 atom, or nitrogen, 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; which process comprises (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an acid derivative ethenylboronové having the general formula (HO) ₂ B ^ \ _{R 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 an alkali metal, and isolating the first intermediate having the general formula

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

(c) reacting a 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 that are useful in inhibiting adenosine kinase, pharmaceutical compositions containing such compounds, a method of using such compounds for inhibiting adenosine kinase, as well as novel compounds. 7-disubstituted-4-aminopyrido [2,3-d] pyrimidine.

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

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

In a more preferred embodiment, the adenosine kinase inhibitor of the present invention is the aforementioned compound of formula (I) or (II) wherein R ⁴ is aryl or

J is heteroaryl and substituted versions thereof and R is lower alkyl, aryl, arylalkyl or heteroaryl or substituted versions thereof.

In another embodiment, the present invention relates to the aforementioned compounds of formula (I) and (II), wherein R and R 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 group, 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 two other heteroatoms selected from O, N, S;

R ³ and R ⁴ are independently selected from the group consisting of:

C 3 -C 6 alkyl,

C2-C6alkenyl,

C2-C6alkynyl,

C 5 -C 6 cycloalkyl, heteroarylC 0 -C 6 alkyl or substituted heteroaryl C 0 -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 2 or substituted 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 -C ₆ alkyloxyC 1 -C ₆ alkyl, arylC ₀ -C ₆ alkyl, arylC 1 -C ₆ alkyloxy, R _{6 (} NCCO), cyano groups, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C 1 -C 6 alkyl, C ₂ -C ₆ alkenyldialkylmalonyl, CF ₃ , groups -OH, C 1 -C 6 alkykyloxyC 1 -C 6 alkyloxy, C 1 -C 6 alkylSO _n , 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 , N-formyl (hetero cyclic), NO ₂ , NR ⁵ 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 C 6 alkylC (O), CF ³ C (O), NR ⁷ R ⁸ C, C ⁶ alkylQO), phthalimidoC 1 -C ₆ C (O), C 1 -C ₆ alkylSOn, wherein n is 1-2, CNC, -C ₆ alkyl, R ⁷ R ⁸ NC ( O) ^NR7 -, heteroaryl, NR ⁷ R ⁸ C _r C6alkylC (O), C CóalkyloxykarbamidoCi-Cealkylu, wherein R ⁷ and R ⁸ are independently selected from those variables which are intended for the substituents R ⁵ and R ^6, or R ⁵ and R ⁶ or R ^{7 a}

R may be taken together with the nitrogen atom 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 (I), the dashed line indicates an optionally present double bond. The present invention also includes those compounds having R ³ and R ⁴ substituents independently selected from those listed below as 6-substituted groups 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 [2,3d] pyrimidine;

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

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

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

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

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

4-amino-6- (4-methylphenyl) -7- (3,4-methylenedioxyphenyl) pyrido [2,3-d] pyrimidine; 4-Amino-6-butyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-Amino-6-butyl-7- (thiophen-3-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-bromothiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-methylthiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (trifluoromethoxy) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-phenoxyphenyl) pyrido [2,3-d] pyrimidine;

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

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

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

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

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

4-Amino-6- (4-methyl-phenyl) -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-nitrothiophen-2-yl) pyrido [2,3-d] pyrimidine;

4-amino-6- (4-methylphenyl) -7- (5-nitrothiophen-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-amino-6-hexyl-7- (4- (dimethylamino) phenyl) pyrido [2,3d] 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;

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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 [2,3d] 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) pyrido [2,3-d] pyrimidine;

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

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

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

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

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

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

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

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

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

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

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

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 [2,3d] 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 [2,3d] 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 [2,3d] 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-bromophenyl) -7- (4-N, N-dimethylaminophenyl) pyrido [2,3d] pyrimidine;

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

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

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

4-amino-6- (4-methylphenyl) -7- (3-methoxyphenyl) pyrido [2,3d] 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) via catalytic hydrogenation or other known reduction processes to produce the compounds as above wherein: The 6, 7 and / or 7,8 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.

In addition, the substituents R ³ and R ⁴ may be independently selected from the group consisting of 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- (1-pyrrolidinyl) -5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3- (dimethylamino) phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4- (dimethylamino) phenyl; 3-methoxyphenyl; 3-methyl-4- (N-acetyl-N-methylamino) phenyl; 3-methyl-4- (N-formyl-N-methylamino) phenyl; 3-methyl-4- (N-methyl-N (trifluoroacetyl) amino) phenyl; 3-methyl-4- (N-methylamino) phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4 (acetylamino) phenyl; 4- (dimethylamino) -3-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 · ft-methylamino) phenyl; 4- (N-ethyl-N-formylamino) phenyl; 4- (N-ethylamino) phenyl; 4- (N-formIN- (2-methoxyethyl) amino) phenyl; 4- (N-isopropylamino) phenyl; 4- (N-methyl-N - ((2-dimethylamino) ethyl) amino) phenyl; 4- (N-methyl-N- (2- (N-phthalimidyl) acetyl) amino) phenyl; 4- (N-methyl-N- (2-cyano) ethylamino) phenyl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-methyl-N- (3-methoxy) propionylamino) phenyl; 4- (N-methyl-N-acetylamino) phenyl; 4- (N-methyl-N-formylamino) phenyl; 4- (N-methyl-N-trifluoroacetylamino) phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophen-2-yl) phenyl; 4- (ureido) phenyl; 4- (2 (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetylamino) ethyl) amino) phenyl; 4- (2-methoxy) ethoxyphenyl; 4- (2-oxo-1-oxazolidinyl) phenyl; 4- (4-methoxy-2-butyl) phenyl; 4- (4-methylpiperidinyl) phenyl; 4- (5-pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4-diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4-methylsulfonylphenyl; 4-morpholinylphenyl; 4-N- (2- (dimethylamino) ethyl) N-formylamino) phenyl; 4-N- (3-methoxypropionyl) -N-isopropylamino) phenyl; 4-N-ethyl-N- (2-methoxyethyl) amino) phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4-piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino) thiophen-2-yl; 5 amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3-dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6- (N-methyl-N-formylamino) -3-pyridinyl; 6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl; 6- (2-oxo-oxazolidinyl) -3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl) -3-pyridinyl; and (4-formylamino) phenyl; (thiophen-2-yl) methyl; (thiophen-3-yl) methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; 1- (3-bromophenyl) ethyl; 2- (N-phenylmethoxycarbonyl) aminophenyl; 2- (3-bromophenyl) ethyl; 2- (3-cyanophenyl) methyl; 2- (4-bromophenyl) ethyl; 2- (5-chloro-2- (thiophen-3-yl) phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3- (furan-2) 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-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5 -trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacryphenyl; 3-trifluoromethyoxyphenyl; Vinylpyridinylphenyl; 3,4-dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di ( trifluoromethyl) phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4benzyloxyphenyl; 4-bromophenyl; 4-bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl or other groups as specified herein.

The term acyl, as used herein, refers to a moiety attached by a carbonyl linkage such as lower alkyl-carbonyl or aryl-carbonyl, in which 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 others as specified herein.

The term aryl or substituted aryl as used herein refers to a carbocyclic aromatic radical including, for example, phenyl and 1-naphthyl or 2-naphthyl, which may be unsubstituted or substituted independently by substituting C1, Br, F for one, two or three hydrogen atoms. I, 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-Nmethoxy) ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4-methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4-methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl , 3-methylsulfonylphenyl, 3-carboxamidopropylphenyl 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.

·· ···· · Λ '«·

The term aryloxy refers to an aryl radical that is attached to the molecule via 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 5 -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 cyclopropylmethyl, 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 additional heteroatoms independently selected from S, O and N; and the remaining atoms in the ring are carbon, a radical that is linked to the rest of the molecule via any atoms in the ring. The heteroaryl group may be unsubstituted or substituted by independently replacing one, two or three hydrogen atoms with Cl, Br, F, I, cyano, carboxamido, hydroxy, lower alkoxy, lower alkyl, lower alkenyl, lower alkynyl, amino, lower alkylamine, di ( lower alkylamine), N-lower alkyl-N-lower alkoxyamine, 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, benzofurofuranyl, benzofurofuranyl , etc., and others as shown herein.

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 additional heteroatoms independently selected from S, O and N; and the remaining are carbon atoms, a radical that is attached to the remainder of the molecule via 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, halo (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 in which the amino group may be further substituted with alkanoyl of from one to eight carbon atoms, an α-amino acid or polypeptide. Examples of the heterocyclic group include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine, and those additionally described herein.

The term heterocyclic-lower alkyl refers to a lower alkyl radical, as defined below, substituted with a heterocyclic group, as defined above, 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, unbranched or branched chain of hydrocarbon radicals containing from one to six carbon atoms inclusive, which may be unsubstituted or substituted by independent replacement of one, two or three carbon atoms with Cl, Br, F groups I, 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, n -butyl, ZerZ-butyl, neopentyl, n -hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, and the like. the C 1 -C 6 alkyl group is described and has a similar meaning as described above for lower alkyl, but is more specifically mentioned. Similarly, the term C 0 -C 6 alkyl indicates carbon atoms that may be present in the alkyl chain including no 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 monounsaturated straight or branched chain hydrocarbon radical containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, 2-butenyl, n-pentenyl and n. -hexenyl. These variables are also referred to as C 2 -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, The (b) butoxy group, the pentyloxy group, the hexyloxy group, the isomeric forms thereof, and the like. This term is also described as C1-C6alkyloxy. .

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, n -petnynyl and n -hexynyl. This term is also described as C2-C6alkynyl.

The term mammal has its normal meaning and includes humans.

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

The present invention encompasses one or more compounds as set forth above formulated into formulations together with one or more non-toxic, physiologically compatible or acceptable diluents, carriers, adjuvants or vehicles, collectively referred to herein as diluents for parenteral injection, for oral administration. administration in solid or liquid form, for rectal or topical administration, and the like. As is 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 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 dosage 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; it is preferred to treat the chronic disorders by the oral route with a tablet or sustained release formulation.

A 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, which may be branched or linear, amino acids are selected independently from such naturally occurring amino acids as glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine , omithine, 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 greater detail below.

The term "substituted versions thereof" refers to those generic groups such as aryl or heteroaryl or heterocycle having substituents on aryl, heteroaryl, heterocyclic or other types that are varied at chemically acceptable positions and as named or exemplified herein .

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, cyclopentanpropionate, digluconate, dodecylsulfate, ethanesulfonate, flavianate, fumarate, glucose, fumarate, glucohep, , heptonate, hexonoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleat, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalat, palmat, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivucate, soda, propionate , thiocyanate, p-toluenesulfonate and undecanoate.

Suitable cationic salts are also readily prepared by conventional procedures such as reacting an acid of formula (I) 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; dialkylsulfates; long chain halides 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 also obtained in this way.

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 solvent combinations.

• · · · · ·

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 a 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, etc.), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyloleate . The fluidity itself can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

These compositions may also contain adjuvants such as a preservative, wetting, emulsifying and dispersing agent. Prevention of the action of microorganisms may be provided by various antibacterial and antifungal agents such as 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. 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 can 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 acacia; (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 also contain a buffering agent.

Solid compositions of a similar type may also 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 a pacifying agent and may also be free of such compositions that release the active compound or compounds in a certain portion of the intestinal tract to some extent delayed. Examples of embedding compositions that can be used are polymeric substances and waxes.

The active compounds 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, 1,3butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germinated 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 adjuvants such as detergents, emulsifying and suspending agents, liming neutralizing agents, flavoring agents, and perfuming agents.

The 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, etc.

Formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a wax suppository that 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 the invention further include ointments, pastes, creams, liquid form for external use, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention. The active 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 agent or with a 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 inhibiting agents or barriers. Ophthalmic formulations, eye ointments, dusting powders and solutions are also intended to be within the scope of this invention.

The present compounds may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolamellar or multilamellar hydrated liquid crystals which 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. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), page 33 et 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 ³ and R ⁴ are as defined above, if not noted.

Scheme ¹

4 5

In accordance with Scheme 1, compounds of formula (II) are prepared wherein R and R are hydrogen. The starting material 4,6-diamino-5-iodopyrimidine (1) is reacted with an ethenylboronic acid derivative (2) wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, a heterocyclic group or heteroaryl; substituted substituted versions thereof, in the presence of tetrakistriphenylphosphopalladium or other suitable palladium-aqueous alkali metal or potassium bicarbonate complex, for example preferably buffered 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. The compound of formula (2) can be prepared by reacting R ³ -substituted acetylene with catecholborane in such a form.

...... ...... * solvents such as THF. R ³ -substituted acetylenes can be prepared according to various literature procedures such as, for example, Van Hijfte et al., Tetrahedron Letters,

1989, 30; 3655; Tao et al. J. Org. Chem., 1990, 55, 63; and Rossi et al., Gazz. Chim. Italian.,

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,

1,2,4-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 a carbon-carbon double bond at 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 and R are lower alkyl, arylalkyl or acyl can be prepared by reacting compound (5) with a suitable reagent. It is possible to prepare a desired derivative of a compound of formula (I) wherein R and R are both hydrogen from a compound of formula (I) or (II) in which R and R are not hydrogen. When the substituent R or R ^{2 is} lower alkyl may be the preparation of the compounds achieved by reacting the free amino group with a suitable alkylating agent such as alkyl halide, alkyl methanesulfonates, or alkyl polyglycosides, toluenesulfonate, in the presence of a base such as triethylamine or potassium carbonate in a suitable rozpoštědle such as methylene chloride or THF. When the substituent R or R is acyl, the preparation of the compounds can be achieved by reacting the free amino group with a suitable, for example, an arylalkyl halide, an alkyl methanesulfonate or an alkyl-p-alkyl group.

toluene sulfonate, 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 the 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 acylcyanide, 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, for example by reacting chloro compounds with monosubstituted or disubstituted amines such as diethylamine, allylamine, dibutylamine. This reaction is readily carried out in a solvent such as methylene chloride in the presence of a tertiary amine. A precursor having a halogen atom instead 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) of Scheme 1) and following the procedure of Scheme 1.

Method for inhibiting kinase

In another aspect of the present invention, there is provided a method of inhibiting adenosine kinase.

In accordance with this method, 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 the method are the same as those previously mentioned. Means for determining an effective inhibitory amount are well known in the art.

The adenosine kinase may be localized in vitro, in situ, or in vivo to be inhibited. Where adenosine kinase is located 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 in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the inhibitor for a period of time and under appropriate physiological conditions. Means for determining maintenance times are well known in the art and will matter.

among other things, also on enzyme concentrations and physiological conditions. Suitable physiological conditions are those necessary to maintain the viability of adenosine kinase and include temperature, acidity, tonicity, and the like. Inhibition of adenosine kinase can be performed, for example, according to standard procedures well known in the art (Yamada et al., Comp. Biochem. Physiol. 1982, 71B): 367-372).

Where adenosine kinase is localized in situ 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 vivof 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 a therapeutically effective amount of a compound of the invention is meant a sufficient amount of the compound to effect or ameliorate appropriate adenosine kinase disorders or those diseases or conditions that are ameliorated by adenosine kinase inhibition and elevated adenosine levels, at a reasonable benefit / risk ratio applicable to any medical treatment. However, it will be understood 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; use of a specific preparation; age, body weight, overall health, gender and lifestyle of the patient; the time of administration, the mode of administration and the rate of excretion of the specific compound used; the duration of the treatment; administering the drugs in combination or identity to the specific compound used; and similar factors well known in the medical practice and skills 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 cells IMR-32 are cultured in the presence and absence of inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or externally applied ¹⁴ C-adenosine 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 adenosine kinase

adenosine binding A1 and A2a receptor, on adenosine deaminase activity and on adenosine transport.

The compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo. Numerous animal models for studying adenosine kinase activity and affects for inhibiting such activity are well known in the art. Examples are adenosine kinase inhibitors that have been reported to protect rodents (such as mice and rats) from seizures induced by subcutaneous administration of pentylentetrazole (PTZ). Typically, rodents are injected with various doses of inhibitor administered followed by, at different times, 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 administering the drug (30 pmol / 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 relative to the vehicle alone having 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 additional investigations described below.

Examining the mouse for the 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 pretreatment, the mice are placed individually in an 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 enclosure on top of a copper plate heated to 55 ° C. Infrared sensors, located near the top of each enclosure, detect the intersection of rays that occur when the mice do not touch the heated surface. The latency times for each jump are automatically recorded, and the latencies for the first and tenth jump are used for data analysis. Mice that do not meet the jump criteria of 180 seconds are immediately moved from the hot plate to avoid tissue damage and are assigned a maximum value of 180 seconds as their 10th jump latency.

Numerous other animal models of adenosine kinase activity have been described [See, for example, Davies et al., Biochem. Pharmacol., 33: 347-355 (1984); Keil et al., Eur. J. Pharmacol., 271: 37-46 (1994); Murray, et al., Drug Development Res., 28: 410-415 (1993)].

Numerous 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 below in Table 1. The data show that the compounds inhibit adenosine kinase.

Table 1

Inhibition of adenosine kinase by representative compounds of the invention

Compounds of Example Number IC ₅₀ (nM) 2 73 3 '185 6 467 9 115 10 317 15 Dec 11 36 250 38 45 55 5 59 117 62 30 63 200 78 25 98 95 103 33 104 8

Method of treating cerebral ischemia, epilepsy, nociperception (nociception) (pain), inflammation including such conditions as septic shock caused by sepsis infection

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

In certain disorders, changes in the cellular activity of adenosine kinase have been observed. Adenosine kinase activity has been found to decrease relative to normal liver in various rat hepatomases: enzyme activity providing a negative correlation with tumor growth rate (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, USA).

et al., Br. J. Cancer, 1978, 37: 701-713). Erythrocyte adenosine kinase activity was found to be 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 subjects at high risk compared to normal healthy controls (Renouf, et al., Clin. Chem. 1989, 35: 14781481). It has been suggested that measurement of adenosine kinase activity is useful in demonstrating the clinical development of patients with HIV infection (Renouf, et al., Clin. Chem. 1989, 35: 1478-1481). Sepsis infection can 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 due to 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, since administration of adenosine or an analog thereof has been demonstrated to result in antinociception or antinociperception (Swaynok, et al., Neuroscience, 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 formulation of 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 phenyl ether with 1.2 equivalent of 4- (dimethylamino) benzaldehyde (Reagent ⁴ ,, R ,,) and 1.5 g 4 · Α molecular sieve. 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] ⁺ .

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

• · • · la. 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 2 M solution of Na 2 SO 2 (15 ml) 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%).

B lb. 2-Phenylethenylboronic acid (reagent "R")

Phenylacetylene (5 mmol, Aldrich) was dissolved in 5 mL dry THF and added dropwise catheterolborane (5 mL, 1 M in THF, Aldrich) at 0 ° C. The solution was heated to reflux for 1.5 hours and the solvent was 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 1 M 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 is subjected to column chromatography (using 5% MeOH, CH 2 Cl 2 as eluent) to afford the desired compound. MS m / z: 213 (M + H) < + & gt ^; .

Examples 2-107

The following procedures of Example 1, except for the substituting reagents specified in Table 1 below for the reagents R ⁴ and R ^{3 of} Example 1, were used to prepare the compounds of Examples 2-107.

C. Ex · Name reagent R ⁴ (position # reagent R ³ (position 6) Data 2 4-Amino-6- (4- methylphenyl) -7- (4- dimethylamino) phenyl) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR (KBr) 3360, 1660, 1600, 1185, found 346 [M + H] ⁺ .

• · · · · · · · · · · · · · · · · · · · · · · · ·

3 4-Amino-6- (4- (dimethylamino) phenyl ) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (4- dimethylaminophenyl) - ethenyl-boronic acid 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- djpyrimidine 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- bromophenyl) pyrido [2,3 -djpyrimidine 4-bromobenzaldehyde 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 ) -7- (4- pyridinyl) pyrido [2,3-d] pyrimidine pyridin-4- carboxaldehyde 2- (4- dimethylaminofen yl) -ethenyl-boronic acid acid IR (microscope) 3320, 1608, 1560, 1521, 1410, 1344, 818 cm ^-1 ; MS m / z 343 [M + H] ⁺ . 7 4-Amino-6- (4- (dimethylamino) phenyl ) -7- (4- bromophenyl) pyrido [2,3 djpyrimidine 4-bromobenzaldehyde 2- (4- dimethylaminofen yl) -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) benzalde hyd 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3360, 3160, 1600, 1555, 1410, 1345, 820; MS W + 391 [M + H] ⁺ . 9 4-Amino-6- (4- methylphenyl) -7- (4- (2- (2- pyridinyl) ethenyl) phen yl) pyrido [2,3- d] pyrimidine 4- (2- (2- pyridinyl) ethenyl) ben zaldehyde 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 [2,3d] pyrimidine 3- pyridinecarboxaldehyde 2- (4-Methylphenyl) ethenyl) boronic acid acid IR 3320, 3360, 3040, 1640, 1550, 1340, 815; MS m / z 314 [M + H] < + ^> . 11 4-Amino-6- (4- methylphenyl) -7- (thiophene-3- yl) pyrido [2,3- djpyrimidine 3- thiophenecarboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3440, 3320, 3160, 3100, 1600, 1555, 1335; MS m / z 319 (M + H) < + & gt ^; . 12 4-Amino-6- (4- methylphenyl) -7- (thiophene-2- yl) pyrido [2,3- d] pyrimidine 2- thiophenecarboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3460, 3360, 3310, 300, 1600, 1555, 1425; MS m / z 319 (M + H) < + & gt ^; . 13 4-Amino-6- (4- methylphenyl) -7- (2- pyridinyl) pyrido [2,3- djpyrimidine 2- pyridinecarboxaldehyde 2- (4-methylphenyl) ethenylboronic acid IR 3440, 3320, 3170, 1640, 1600, 1555, 1340; MS m / z 314 (M + H) < + & gt ^; . 14 4-Amino-6- (4- methylphenyl) -7- (3,4- methylenedioxyphenyl) pyrido [2,3- djpyrimidine 3,4- methylenedioxybenzal dehyd 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3365, 3120, 1600, 1555, 1440, 1250, 1040; MS m / z 357 (M + H) < + & gt ^; .

• · · · · · · · · · · ·

15 Dec 4-Amino-6-butyl-7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine 2- thiophenecarboxaldehyde 1-hexenylboronic acid acid IR 3320, 3160, 2955, 2860, 1640, 1560, 1335; MS m / z 285 (M + H) < + & gt ^; . 16 4-Amino-6-butyl-7 (thiophen-3-yl) pyrido [2,3-d] pyrimidine 3- thiophenecarboxaldehyde 1-hexenylboronic acid acid IR 3300, 3070, 2950, 2850, 1600, 1565, 1330; MS m / z 285 (M + H) < + & gt ^; . 17 4-Amino-6- (4-methylphenyl) -7- (5-bromothiophen-2-yl) pyrido [2,3-d] pyrimidine 5-Bromothiophene-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3450, 3100, 3100, 1640, 1600, 1555, 1425; MS m / z 397/399 (M + H) < + & gt ^; . 18 4-Amino-6- (4- methylphenyl) -7- (5- methylthiophen-2-yl) pyrido [2,3-d] pyrimidine 5-Methylthiophene-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3460, 3380, 3300, 3150, 1640, 1555, 1445; MS m / z 333 (M + H) < + & gt ^; . 19 Dec 4-Amino-6- (4-methylphenyl) -7- (4-trifluoromethoxy) phenyl) pyrido [2,3-d] pyrimidine 4- (trifluoromethyl) benza ldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3440, 3320, 3180, 1555, 1490, 1340, 820; MS m / z 397 (M + H) < + & gt ^; . 20 May 4-Amino-6- (4- methylphenyl) -7- (3- phenoxyphenyl) pyrido [2, 3-d] pyrimidine 3-Phenoxybenzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3400, 3180, 3050, 1555, 1340, 1255, 820; MS m / z 405 (M + H) < + & gt ^; . 21 4-Amino-6- (4- methylphenyl) -7- (5- nitrothiofen-2- yl) pyrido [2,3- d] pyrimidine 5-nitro-thiophene-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3380, 3100, 1595, 1550, 1330, 1260, 815; MS m / z 364 (M + H) < + & gt ^; . 22nd 4-Amino-6- (4- methylphenyl) -7- (4- bromthiofen-2- yl) pyrido [2,3- djpyrimidine 4-Bromo-thiophene-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3320, 3100, 1595, 1555, 1415, 1340, 820; MS m / z 397/399 (M + H) < + & gt ^; .

• · ·

23 4-Amino-6- (4- methylphenyl) -7- (3- methylthiofen-2- yl) pyrido [2,3- djpyrimidine 3-Methyl-thiophene-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3300, 3060, 1600, 1550, 1450, 1335, 820; MS m / z 333 (M + H) < + & gt ^; . 24 4-Amino-6- (4- methylphenyl) -7- (furan-2- yl) pyrido [2,3- djpyrimidine furan-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3430, 3300, 3170, 1630, 1560, 1450, 1340; MS Wz 303 (M + H) < + & gt ^; . 25 4-Amino-6- (4- methylphenyl) -7- (furan-3- yl) pyrido [2,3- djpyrimidine furan-3- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3360, 3140, 1655, 1605, 1555, 1340, 1165; MS m / z 303 (M + H) < + & gt ^; . 26 4-Amino-6- (4-methylphenyl) -7- (5-methyl-furan-2-yl) -pyrido [2,3d] pyrimidine 5-Methylfuran-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3460, 3320, 3160, 2960, 1600, 1555, 1330, 392; MS m / z 317 (M + H) < + & gt ^; . 27 Mar: 4-Amino-6- (4- (2-propyl) phenyl) -7 (thiophen-2-yl) pyrido [2,3-d] pyrimidine thiofen-2- carboxaldehyde 2- (4- (2-propyl) phenyl) - ethenyl-boronic acid acid IR 3440, 3180, 1630, 1600, 1555, 1355, 820; MS m / z 317 (M + H) < + & gt ^; . 28 4-Amino-6- (4- (2- propyl) phenyl) -7- (5- nitrothiofen-2- yl) pyrido [2,3- djpyrimidine 5-nitro-thiophene-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) < + & gt ^; . 29 4-Amino-6- (4- methylphenyl) -7- (5- nitrothiofen-2- yl) pyrido [2,3- dlpyrimidine 5-nitro-thiophene-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3330, 3160, 1630, 1600, 1555, 1350, 810; MS m / z 348 (M + H) < + & gt ^; . 30 4-Amino-6- (4- (dimethylamino) phenyl ) -7- (thiophen-2-yl) - pyrido [2,3-d] - pyrimidine thiofen-2- carboxaldehyde 2- (4- (dimethylamino) phenyl -ethenyl-boronic acid acid IR 3440, 3160, 1610, 1555, 1525, 1340, 820; MS m / z 348 (M + H) < + & gt ^; .

31 4-Amino-6- (3,4- dimethoxyphenyl) -7- (thiophene-2- yl) pyrido [2,3- d] pyrimidine thiofen-2- carboxaldehyde 2- (3,4- dimethoxyphenyl) - ethenyl-boronic acid acid IR 3420, 3080, 1600, 1560, 1515, 1425, 1340; MS m / z 365 (M + H) ⁺ . 32 4-Amino-6- (3,4- dimethoxyphenyl) -7- (5-nitrothiophene-2- yl) pyrido [2,3- djpyrimidine 5-nitro-thiophene-2- carboxaldehyde 2- (3,4- dimethoxyphenyl) - ethenyl-boronic acid acid IR 3420, 2840, 1600, 1555, 1515, 1335, 1255; MS m / z 410 (M + H) < + & gt ^; . 33 4-Amino-6-hexyl-7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 1-octenylboronic acid acid IR 3320, 300, 2920, 2850, 1600, 1560, 1335; MS m / z 350 (M + H) < + & gt ^; . 34 4-Amino-6-hexyl-7- (thiophene-2- yl) pyrido [2,3- djpyrimidine thiofen-2- carboxaldehyde 1-octenylboronic acid acid IR 3320, 3160, 2920, 2840, 1600, 1560, 1425; MS m / z 313 (M + H) < + & gt ^; . 35 4-Amino-6- (2-methyl- 2-propyl) -7- (thiophene- 2-yl) pyrido [2,3- d] pyrimidine thiofen-2- carboxaldehyde 3,3-dimethyl-1- butenylboronic acid acid IR 3400, 3320, 3180, IR 2960, 1640, 1565, 1335; MS m / z 285 (M + H) < + & gt ^; . 36 4-Amino-6- (4- (2- propyl) phenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 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) < + & gt ^; . 37 4-Amino-6- (4- propylphenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (4-Propylphenyl) - ethenyl-boronic acid acid IR 3520-3250, 2960, 1590, 1555, 1400, 1340, 1195, 815; MS m / z 384 (M + H) ⁺ .

• 4 • «· · · ·

38 4-Amino-6- (3,4- dimethoxyphenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3,4- dimethoxyphenyl) - ethenyl-boronic acid acid IR 3320, 3240-2760, 1590, 1560, 1510, 1515, 1340; MS m / z 820 (M + H) < + & gt ^; . 39 4-Amino-6- (3- methoxyphenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3-Methoxyphenyl) - ethenyl-boronic acid acid IR 3365, 3220, 3250-2780, 1660, 1590, 1560, 1460, 1400, 1200, 820; MS m / z 402 (M + H) < + & gt ^; . 40 4-Amino-6- (3- bromophenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - 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) < + & gt ^; . 41 4-Amino-6- (3- fluorophenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- d] pyrimidine 4- (dimethylamino) - 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) < + & gt ^; . 42 4-amino-6- (3-trifluoromethylphenyl) - 7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3- trifluoromethylphenyl) - ethenyl-boronic acid acid IR 3560, 3520, 3240-2840, 1660, 1590, 1560, 1400, 1340, 1160, 1120, 810, 700; MS m / z 410 (M + H) ⁺ . 43 4-Amino-6- (3- chloromethylphenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - 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) < + & gt ^; .

• »

44 4-Amino-6- (3,5-dichlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine 4- (dimethylamino) - benzaldehyde 2- (3,5-dichlorophenyl) - ethenyl-boronic acid acid IR 3560-3280, 3240-3300, 1640, 1590, 1560, 1400, 1365, 1340, 1195, 820, 800; MS m / z 411 (M + H) < + & gt ^; . 45 4-Amino-6- (3,4- methylenedioxyphenyl) - 7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3,4- methylenedioxyphenyl) - ethenyl-boronic acid acid IR 3600-3280, 3240-3000, 1595, 1560, 1400, 1195, 1040, 815; MS m / z 386 (M + H) < + & gt ^; . 46 4-Amino-6- (3,4- methylenedioxyphenyl) - 7- (thiophene-2- yl) pyrido [2,3- djpyrimidine thiofen-2- carboxaldehyde 2- (3,4- methylenedioxyphenyl) - ethenyl-boronic acid acid IR 3430, 3300, 3170, 1630, 1595, 1575, 1450, 1425, 1035, 820; MS m / z 349 (M + H) < + & gt ^; . 47 4-Amino-6- (3- methoxycarbonylphenyls 1) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3- methoxycarbonylphenyls l) -ethenyl-boronic acid acid IR 3360, 3320, 3200-3000, 1720, 1660, 1595, 1560, 1400, 1340, 1200, 820; MS m / z 400 (M + H) < + & gt ^; . 48 4-Amino-6- (3- (2- propyl) phenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 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) < + & gt ^; . 49 4-Amino-6- (4- (2- methyl-2- propyl) phenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - 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) < + & gt ^; . 50 4-Amino-6- (4-fluorophenyl) -7- (4 (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine 4- (dimethylamino) - benzaldehyde 2- (4-fluorophenyl) - ethenyl-boronic acid acid IR 3490, 3320, 3200-3000, 1590, 1555, 1400, 1340, 1195, 820; MS m / z 360 (M + H) < + & gt ^;.

K k k k k a a a a a a a k k k k k k k k k k

51 4-Amino-6- (4-methoxyphenyl) -7- (4 (dimethylamino) phenyl) pyrido [2,3d] pyrimidine 4- (dimethylamino) - benzaldehyde 2- (4-Methoxyphenyl) - ethenyl-boronic acid acid IR 3370, 3320, 3200-3000, 1660, 1590, 1555, 1400, 1340, 1250, 1195, 815; MS m / z 372 (M + H) < + & gt ^; . 52 4-Amino-6- (3- (phenylmethoxy) phenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3- (phenylmethoxy) phenyl) -ethenyl-boronic acid acid IR 3360, 3320, 3200-3000, 1665, 1590, 1560, 1400, 1195, 820; MS m / z 448 (M + H) < + & gt ^; . 53 4-Amino-6- (4- chlorophenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (4-chlorophenyl) - ethenyl-boronic acid acid IR 3480-3320, 3200-3020, 1590, 1550, 1410, 1340, 1195, 815; MS m / z 376 (M + H) < + & gt ^; . 54 4-Amino-6- (3-fluoro-4- methylphenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- d] pyrimidine 4- (dimethylamino) - benzaldehyde 2- (3-fluoro-4- methylphenyl) -ethenyl- boronic acid IR 3360, 31603000, 1660, 1590, 1555, 1340, 1200, 820; MS m / z 374 (M + H) < + & gt ^; . 55 4-Amino-6- (3-fluoro-4- methylphenyl) -7- (4- (thiophene-2- yl) phenyl) pyrido [2,3- d] pyrimidine 4- (thiophene-2- caroboxaldehyde) - benzaldehyde 2- (3-fluoro-4- methylphenyl) -ethenyl- boronic acid IR 3600-3300, 3200, 3020, 1620, 1415; MS m / z 337 (M + H) < + & gt ^; . 56 4-Amino-6- (3- phenylpropyl) -7- (4- (methoxyphenyl) phenyl) pyrido [2,3- d] pyrimidine 4- methoxybenzaldehyde 5-Phenyl-1-pentenyl- boronic acid NMR (CDC1 ₃₎ δ 8.70 (s, IH), 8.06 (s, IH), 7.53 (d, J = 9Hz, 2H), 7.22 (m, 3H), 7.06 (d, J = 8Hz, 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) < + & gt ^; .

• · · ·

57 4-Amino-6- (3- phenylpropyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- d] pyrimidine 4- (dimethylamino) - benzaldehyde 5-Phenyl-1-pentenyl- boronic acid NMR (CDC1 ₃₎ δ 8.73 (s, IH), 7.88 (s, IH), 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), 2.96 (m, 2H), 2.61 (t, J = 8Hz, 2H), 1.91 (m, 2H) ; MS m / z 384 (M + H) < + & gt ^; . 58 4-Amino-6- (2- phenylethy1) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 4-Phenyl-1-butenyl- boronic acid NMR (CDCl3) δ 8.75 (s, 1H), 7.69 (s, 1H), 7.65 (m, 2H), 7.21 (m, 2H), 7.04 (m, 2H), 6.79 (m, 2H), 5.57 (s) br, 2H), 3.25 (m, 2H), 3.04 (s, 6H), 2.85 (m, 2H) ,; MS m / z 370 (M + H) < + & gt ^; . 59 4-Amino-6 (phenylmethyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine 4- (dimethylamino) - benzaldehyde 3-Phenyl-1-propenyl- boronic acid NMR (CDCl3) δ 8.74 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 9 Hz, 2H), 7.30 (m, 3H), 7.10 (m, 2H), 6.74 (d, J = 9Hz, 2H), 5.64 (s, br, 2H), 4.29 (s, 2H), 3.02 (s, 6H) ,; MS m / z 356 (M + H) < + & gt ^; .

• 9 * · 99 · 9 «

9999 * 9 ··

9

9 9 9 9 999

9 9 9

99 99 <9

60 4-Amino-6- (cyclohexylmethyl) - 7- (4- (dimethylamino) phenyl ) pyrido [2,3- d] pyrimidine 4- (dimethylamino) - benzaldehyde 3-Cyclohexyl-1- propeny 1-boron acid NMR (CDCl3) δ 8.75 (s, 1H), 7.90 (s, 1H), 7.59 (d, J = 9 Hz, 2H), 6.76 (d> 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)) b) l) pyrido [2,3-d] pyrimidine 4- (dimethylamino) - benzaldehyde 3-hexenylboronate acid NMR (CDCl3) 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- djpyrimidine 4- (dimethylamino) - benzaldehyde 3-Heptenylboronate acid NMR (DMSOd6) δ 8.53 (s, 1H), 8.45 (s, 1H), 7.47 (d, J = 8Hz, 2H), 6.82 (d, J = 8Hz, 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 ^; .

99

63 4-Amino-6- (2- methylpropyl) pentyl- 7- (4- (dimethylamino)) phenyl) pyrido [2,3-d] pyrimidine 4- (dimethylamino) - benzaldehyde 4-Methyl-1-pentenyl- boronic acid NMR (CDCl ₃ ) δ 8.76 (s, 1H), 7.88 (s, 1H), 7.61 (d, J = 9 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 5.76 (s, br, 2H) 3.03 (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- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 1-pentenylboronic acid acid NMR (DMSOd6) 58.52 (s, 1H), 8.45 (s, 1H), 7.90 (s, br, 2H), 7.48 (d, J = 8Hz, 2H), 6.82 (d, J = 8Hz, 2H), 2.99 (s, 6H), 2.80 (m, 2H), 1.60 (sextet, J = 7Hz, 2H), 0.85 (J = 7Hz, 3H); MS m / z 308 (M + H) &lt; + & gt ^; . 65 4-Amino-6- (3- cyanopropyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 5-Cyano-1-pentenyl- boronic acid NMR (DMSOd6) 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), 3.00 (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- nitrophenyl) -7- (4- (dimethylamino) phenyl ) pyrido [2,3- djpyrimidine 4- (dimethylamino) - benzaldehyde 2- (3- nitophenyl) ethenyl- boronic acid IR 3360, 3100, 1590, 1560; MS m / z 387 (M + H) &lt; + & gt ^; .

I

• · ·

67 4-Amino-6-pentyl-7 (thiophen-2-yl) pyrido [2,3-d] pyrimidine thiofen-2- carboxaldehyde 1-Heptenylboronic acid IR 3320, 3100, 1560, 1430; MS m / z 299 (M + H) &lt; + & gt ^; . 68 4-Amino-6- (3-carboxamidopropyl) 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-lpyrimidine thiofen-2- carboxaldehyde 2- (4-Methoxyphenyl) - propenyl-boronic acid acid IR 3360, 3100, 1605, 1565; MS m / z 349 (M + H) &lt; + & gt ^; . 70 4-Amino-6 - ((3- bromophenyl) methyl) -7- (thiophene-2- yl) pyrido [2,3- d] pyrimidine thiofen-2- carboxaldehyde 2- (3-Bromophenyl) - propenyl-boronic acid 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- (thiophene-2- yl) pyrido [2,3- dlpyrimidine thiofen-2- carboxaldehyde 2- (4- (2-propyl) phenyl) - propenyl-boronic acid 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) pyrido [2 3-dopyrimidine 4-isopropyl- benzaldehyde 2- (4-Methoxyphenyl) - propenyl-boronic acid acid IR 3360, 3120, 1565, 1510; MS m / z 385 (M + H) &lt; + & gt ^; . 73 4-Amino-6 - ((4- bromophenyl) methyl) -7- (thiophene-2- yl) pyrido [2,3- djpyrimidine thiofen-2- carboxaldehyde 2- (4-Bromophenyl) - propenyl-boronic acid acid IR 3440, 3160, 1625, 1560; MS m / z 397/399 (M + H) &lt; + & gt ^; . 74 4-Amino-6 - ((3- fluorophenyl) methyl) -7- (thiophene-2- yl) pyrido [2,3- djpyrimidine thiofen-2- carboxaldehyde 2- (4-fluorophenyl) - propenyl-boronic acid acid IR 3320, 3160, 1600, 1560; MS m / z 337 (M + H) &lt; + & gt ^; . 75 4-Amino-6 - ((4- bromophenyl) methyl) -7- (thiazole-2- yl) pyrido [2,3- djpyrimidine thiazol-2- carboxaldehyde 2- (4-Bromophenyl) - propenyl-boronic acid acid IR 3450, 300, 1635, 1560; MS m / z 398/400 (M + H) &lt; + & gt ^; .

• ·

• ·

76 4-Amino-6 - ((3- methoxyphenyl) methyl ) -7- (thiophene-2- yl) pyrido [2,3- d] pyrimidine thiofen-2- carboxaldehyde 2- (3-Methoxyphenyl) - propenyl-boronic acid acid IR 3450, 3150, 1600, 1560; MS m / z 349 (M + H) &lt; + & gt ^; . 77 4-Amino-6- (phenylmethyl) -7- (thiophene-2- yl) pyrido [2,3- dlpyrimidine thiofen-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-metho- xyphenyl) methyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3- d] pyrimidine 4- (dimethylamino) - benzaldehyde 2- (3-Methoxyphenyl) - propenyl-boronic acid acid IR 3310, 3080, 1600, 1565; MS m / z 386 (M + H) &lt; + & gt ^; . 79 4-Amino-6- (4-methyl- phenyl) -7- (4- (trifluoro- methyl) phenyl) pyrido [ 2,3-dlpyrimidine 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- (methylphenyl) pyrido [ 2,3-dlpyrimidine 4-methyl- benzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3450, 1449, 1340, 820; MS m / z 327 (M + H) &lt; + & gt ^; . 81 4-Amino-6- (4-methylphenyl) -7- (4-methoxyphenyl) pyrido [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 -dlpyrimidine 4-ethylbenzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid 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-Cyanobenzaldehyde 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- acetamidophenyl) pyrid o [2,3-d] 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) pyrido [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 ^;.

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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 331 (M + H) &lt; + & gt ^; . 88 4-Amino-6- (4- methylphenyl) -7- (4- chlorophenyl) pyrido [2,3 -djpyrimidine 4-chlorobenzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3340, 1550, 1340, 910; MS m / z 347 (M + H) &lt; + & gt ^; . 89 4-Amino-6- (4-methylphenyl) -7- (4-aminophenyl) pyrido [2,3-d] pyrimidine 4-Aminobenzaldehyde 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- methylthiophenyl) pyrid o [2,3-d] 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-Phenylbenzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3345, 1560, 820; MS m / z 389 (M + H) &lt; + & gt ^; . 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) &lt; + & gt ^; . 93 4-Amino-6- (4- methylphenyl) -7 - ((4- N, 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) phenyl) 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 [2,3d] 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- chlorophenyl) pyrido [2,3 -djpyrimidine 4-chlorobenzaldehyde 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-methyl-phenyl) -7- (3,5-dimethoxy-phenyl) -pyrido [2,3-d] 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 ^; .

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98 4-Amino-6- (thiophene-2- yl) -7- (4-X 2 -) dimethylphenyl) pyrido [2,3-d] pyrimidine 4- (ΛζΎ- diethylamino) - benzaldehyde 2- (thiophen-2-yl) - ethenyl-boronic acid acid IR 3320, 1590, 700. MS m / z 348 (M + H) &lt; + & gt ^; . 99 4-Amino-6- (4- methylphenyl) -7- (benzofuran-2- yl) pyrido [2,3- dlpyrimidine benzofuran-2- carboxaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid IR 3310, 1640, 750; MS m / z 353 (M + H) &lt; + & gt ^; . 100 ALIGN! 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 311 (M + H) ⁺ 101 4-Amino-6- (thiophene-2- yl) -7- (4- methoxyphenyl) pyrido [2,3-dlpyrimidine 4- methoxybenzaldehyde 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-A (7H- dimethylphenyl) pyrido [2,3-dlpyrimidine 4- (ΛζΑ- 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-ΛζΑ- dimethylphenyl) pyrido [2,3-dlpyrimidine 4- (ΛζΑ- dimethylamino) - benzaldehyde 2- (3-Bromo-4- methoxyphenyl) - 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- ((thiophene-2- yl) pyrido [2,3- d] pyrimidine thiofen-2- carboxaldehyde 2- (3-Bromo-4- methoxyphenyl) - ethenyl-boronic acid acid IR 3400, 1550, 1280, 715; MS m / z 414 (M + H) &lt; + & gt ^; . 105 4-Amino-6- (4-methylphenyl) -7- (4-butoxyphenyl) pyrido [2,3-d] pyrimidine 4-butoxybenzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid on 106 4-Amino-6- (4- methylphenyl) -7- (3- methoxyphenyl) pyrido [ 2,3-d] pyrimidine 4- methoxybenzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid on 107 4-Amino-6- (4-methylphenyl) -7- (3,5-dichlorophenyl) pyrido [2,3-d] pyrimidine 3,5-dichloro- benzaldehyde 2- (4-Methylphenyl) - ethenyl-boronic acid acid on

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Claims (18)

A compound and pharmaceutically acceptable salts and amides thereof having the general formula (I) 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 forming a five to seven membered ring optionally containing an additional oxygen or nitrogen atom; R ³ and R ⁴ are independently selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or heterocyclic and the dashed line indicates an optional double bond. The compound of claim 1, wherein R ³ is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heteroaryl or a heterocyclic group; and R ⁴ is selected from the group consisting of aryl, arylalkyl, heteroaryl or heterocyclic. 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) 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, S; R ³ and R ⁴ are independently selected from the group consisting of: C 1 -C 6 alkyl, C2-C6alkenyl, C 1 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heteroarylC 0 -C 6 alkyl or substituted heteroaryl C 0 -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 2 or substituted arylC 2 -C 6 alkynyl or substituted arylC 2 -C 6 alkynyl wherein the 1-4 heteroaryl or aryl substituents are independently selected from the group consisting of halogen, cyanoC 1 -C 6 alkyl, heteroaryl, heterocyclic, C 1 -C 6 alkyloxy, C 1 -C 6 alkykyloxyC 1 -C 6 alkyl, arylC 1 -C 6 alkyl, , arylC 1 -C 6 alkykyloxy, 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 6 alkyloxyC 1 -C 6 alkykyloxy, SO _n C 1 -C 6 alkyl, 1-3, C 1 -C ₆ alkylthio, C 1 -C ₆ alkyl acrylic, CF 3 O, CF 3, C 1 -C ₄ alkylenedioxy, C 1 -C ₆ alkyl acrylic, H ₂ N (CO) NH, Nformyl (heterocyclic), NO 2, NR ⁵ R ^{C 6} -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 ₃ C (O), NR ⁷ R ⁸ C ₁ -C ₆ alkylC (O), phthalimidoC 1 -C ₆ C (O), CNC 1 -C ₆ alkyl, H ₃ NC (O) NH-, heteroaryl, NR ⁷ R ⁸ C 1 -C ₆ alkylC (O), C 1 -C 6 alkyloxycarbamidoC 1 -C 6 alkyl, Wherein the substituents R and R are independently selected from those variables that are intended for the substituents R ⁵ and R ⁶ or the substituents R ⁵ and R ^6, or R 8 and R 8 may be taken together with the nitrogen atom to which they are attached to form a five to seven membered ring or optionally containing one to three additional heteroatoms selected from O, N or S, wherein the substituents are selected from C 1-7 Cólalkyl. A compound according to claim 1 wherein R ³ and R ⁴ are independently selected from the group consisting of 4k 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- (1-pyrrolidinyl) -5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3- (dimethylamino) phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4- (dimethylamino) phenyl; 3-methoxyphenyl; 3-methyl-4- (N-acetyl-N-methylamino) phenyl; 3-methyl-4- (N-formyl-N-methylamino) phenyl; 3-methyl-4- (N-methyl-N (trifluoroacetyl) amino) phenyl; 3-methyl-4- (N-methylamino) phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4 (acetylamino) phenyl; 4- (dimethylamino) -3-fluorophenyl; 4- (dimethylamino) phenyl; 4- (imidazol-1-yl) phenyl; 4- (methylthio) phenyl; 4- (morpholinyl) phenyl; 4- (N- (2 (dimethylamino) ethyl) amino) phenyl; 4- (N- (2-methoxyethyl) amino) phenyl; 4- (N-acetyl-N-methylamino) phenyl; 4- (N-ethyl-N-formylamino) phenyl; 4- (N-ethylamino) phenyl; 4- (N-formyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-isopropylamino) phenyl; 4- (N-methyl-N - ((2-dimethylamino) ethyl) amino) phenyl; 4- (N-methyl-N- (2- (N-phthalimidyl) acetyl) amino) phenyl; 4- (N-methyl-N- (2-cyano) ethylamino) phenyl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-methyl-N- (3-methoxy) propionylamino) phenyl; 4- (N-methyl-N-acetylamino) phenyl; 4- (N-methyl-N-formylamino) phenyl; 4- (N-methyl-N-trifluoroacetylamino) phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophen-2-yl) phenyl; 4- (ureido) phenyl; 4- (2 (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetylaminoethyl) amino) phenyl; 4- (2-methoxy) ethoxyphenyl; 4- (2-oxo-1-oxazolidinyl) phenyl; 4- (4-methoxy-2-butyl) phenyl; 4- (4-methylpiperidinyl) phenyl; 4- (5-pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4-diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl; 4-methylaminophenyl; 4-methylsulfonylphenyl; 4-morpholinylphenyl; 4-N- (2- (dimethylamino) ethyl) N-formylamino) phenyl; 4-N- (3-methoxypropionyl) -N-isopropylamino) phenyl; 4-N-ethyl-N- (2-methoxyethyl) amino) phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino) thiophen-2-yl; 5 amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3-dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6- (N-methyl-N-formylamino) -3-pyridinyl; 6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl; 6- (2-oxo-oxazolidinyl) -3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6 • pyrrolidinyl-3-pyridinyl; (2-propyl) -3-pyridinyl; and (4-formylamino) phenyl; (thiophen-2-yl) methyl; (thiophen-3-yl) methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; 1- (3-bromophenyl) ethyl; 2- (N-phenylmethoxycarbonyl) aminophenyl; 2- (3-bromophenyl) ethyl; 2- (3-cyanophenyl) methyl; 2- (4-bromophenyl) ethyl; 2- (5-chloro-2- (thiophen-3-yl) phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3- (furan-2) 3- (thiophen-2-yl) phenyl; 3- (2-pyridyl) phenyl; 3- (3-methoxybenzyl) phenyl; 3- (amino) propynyl; 3-benzyloxyphenyl; 3-bromo-4-fluoro phenyl; 3-bromo-5-iodophenyl; 3-bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-carboxamidophenyl; 3-chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3-methoxyphenyl; 5-trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacryphenyl; 3-trifluoromethyoxyphenyl; 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; dimethylphenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bromothio phen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl. A compound according to claim 1 of the general formula (Π) 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 a 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, S; R ³ and R ⁴ are independently selected from the group consisting of: C 1 -C 6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C 1 -C 6 cycloalkyl, heteroarylC 0 -C 6 alkyl or substituted heteroaryl C 0 -C 6 alkyl, arylC 0 -C 6 alkyl or substituted arylC 0 -C 6 alkenyl or substituted heteroaryl C 2 -C 6 alkenyl, arylC 2 -C 6 alkenyl or substituted C 1 -C 6 alkenyl or substituted C 1 -C 6 alkenyl or substituted C 1 -C 6 alkenyl; -C 0-6 alkynyl or substituted arylC 2 -C 6 alkynyl, wherein the 1-4 heteroaryl or aryl substituents 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, K 3 -C 6 alkylC 1 -C 6 alkyl, -C 6 alkynyloxy, 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 alkylSOn, n is 1- 2, C 1 -C 6 alkylthio, C 1 -C 6 alkylaryl, CF 3 O, CF 3, C 1 -C 4 alkylenedioxy, C 1 -C 6 alkylaryl, R ⁵ R ⁶ N (CO) NR ⁵ , Nformyl (heterocyclic), NO 2, NR ⁵ R ⁶ Co-6 alkyl, wherein the substituents R ⁵ and R ⁶ are independently selected from hydrogen, C Céalkyl, HC (O), C CóalkyloxyCi-COalkyl, C 1 -C ₆ alkyloxy, C 1 -C ₆ alkylC (O), CF ₃ C (O), NR ⁷ R ⁸ C, C ⁶ alkyl C (O), phthalimidoC 1 -C ₆ C (O), C 1 -C 6 alkylSOn, wherein n is 1 -2, CNC 1 -C 6 alkyl, R ⁷ R ⁸ NC (O) NR ⁷ -, heteroaryl, NR ⁷ R ⁸ C 6 -C 6 alkylC (O), C 1 -C 6 alkyloxycarbamidoC 1 -C 6 alkyl, wherein R and R are independently selected from those variables, which are intended for the substituents R ⁵ and R ⁶ or the substituents R ⁵ and R ⁶ or the substituents R and R ⁶ may be joined together with the nitrogen atom to which they are attached to form a five to seven membered 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. 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- (1-morpholinyl) -5-pyrimidinyl; 2- (1-pyrrolidinyl) -5-pyrimidinyl; 2-dimethylamino-5-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl; 2-pyridyl; 3- (dimethylamino) phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4- (dimethylamino) phenyl; 3-methoxyphenyl; 3-methyl-4- (N-acetyl-N-methylamino) phenyl; 3-methyl-4- (N-formyl-N-methylamino) phenyl; 3-methyl-4- (N-methyl-N (trifluoroacetyl) amino) phenyl; 3-methyl-4- (N-methylamino) phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-dichlorophenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4 (acetylamino) phenyl; 4- (dimethylamino) -3-fluorophenyl; 4- (dimethylamino) phenyl; 4- (imidazol-1-yl) phenyl; 4- (methylthio) phenyl; 4- (morpholinyl) phenyl; 4- (N- (2 (dimethylamino) ethyl) amino) phenyl; 4- (N- (2-methoxyethyl) amino) phenyl 4- (N-acetyl-N-methylamino) phenyl; 4- (N-ethyl-N-formylamino) phenyl; 4- (N-ethylamino) phenyl; 4- (N-formyl N- (2-methoxyethyl) amino) phenyl; 4- (N-isopropylamino) phenyl; 4- (N-methyl-N - ((2-dimethylamino) ethyl) amino) phenyl; 4- (N-methyl-N- (2- (N-phthalimidyl) acetyl) amino) phenyl 4- (N-methyl-N- (2-cyano) ethylamino) phenyl; 4- (N-methyl-N- (2-methoxyethyl) amino) phenyl; 4- (N-methyl-N- (3-methoxy) propionylamino) phenyl; 4- (N-methyl-N-acetylamino) phenyl; 4- (N-methyl-N-formylamino) phenyl; 4- (N-methyl-N-trifluoroacetylamino) phenyl; 4- (N-morpholinyl) phenyl; 4- (thiophene- 2-yl) phenyl; 4- (ureido) phenyl; • · 4- (2- (dimethylamino) acetylamino) phenyl; 4- (2- (2-methoxy) acetylaminoethyl) amino) phenyl; 4- (2-methoxy) ethoxyphenyl; 4- (2-oxo-1-oxazolidinyl) phenyl; 4- (4-methoxy-2-butyl) phenyl; 4- (4-methylpiperidinyl) phenyl; 4- (5-pyrimidinyl) phenyl; 4-aminophenyl; 4-bromophenyl; 4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4-diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4-ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-imidazolylphenyl; 4-iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl; 4-methylaminophenyl; 4-methylsulfonylphenyl; 4-morpholinylphenyl; 4-N- (2- (dimethylamino) ethyl) N-formylamino) phenyl; 4-N- (3-methoxypropionyl) -N-isopropylamino) phenyl; 4-N-ethyl-N- (2-methoxyethyl) amino) phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4-piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-butylacrylphenyl; 5- (dimethylamino) thiophen-2-yl; 5 amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl; 3-dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6- (N-methyl-N-formylamino) -3-pyridinyl; 6- (N-methyl-N- (2-methoxyethyl) amino) -3-pyridinyl; 6- (2-oxo-oxazolidinyl) -3-pyridinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-3-pyridinyl; 6-morpholinyl-3-pyridinyl; 6-pyrrolidinyl-3-pyridinyl; (2-propyl) -3-pyridinyl; and (4-formylamino) phenyl; (thiophen-2-yl) methyl; (thiophen-3-yl) methyl; butyl; cycloheptyl; pentyl; thiophen-2-yl; 1- (3-bromophenyl) ethyl; 2- (N-phenylmethoxycarbonyl) aminophenyl; 2- (3-bromophenyl) ethyl; 2- (3-cyanophenyl) methyl; 2- (4-bromophenyl) ethyl; 2- (5-chloro-2- (thiophen-3-yl) phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-phenylethyl; phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3- (furan-2) 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-diethylmalonylallylphenyl; 3-dimethylaminophenyl; 3-ethoxyphenyl; 3-fluoro-5 -trifluoromethylphenyl; 3-fluorophenyl; 3-hydroxyphenyl; 3-iodophenyl; 3methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-methylsulfonylphenyl; 3-methylthiophenyl; 3-t-butylacryphenyl; 3-trifluoromethyoxyphenyl; -dichlorophenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-di (trifluoromethyl) phenyl; 3,5-dibromophenyl; 3,5-dichlorophenyl; 3,5dimethoxyphenyl; -dimethylphenyl; 4- (2-propyl) phenyl; 4- (2-propyl) oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-bromothio phen-2-yl; 4-butoxy phenyl; 4-dimethylaminophenyl; 4-fluoro-3-trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; 5-hexyl; 5-methyl; 5-phenyl; (2-bromo-5-chlorophenyl) methyl; (2-bromophenyl) methyl; and (5-chloro-2- (3-methoxyphenyl) phenyl) methyl. The compound of claim 5, wherein R ³ and R ⁴ are independently selected from the group consisting of: phenyl; 4-dimethylaminophenyl; 4-methylphenyl; 4-bromophenyl; 4-pyridinyl; (5-pyrimidinyl) phenyl; 2- (2-pyridinyl) ethenyl) phenyl; 3-pyridinyl; thiophen-3-yl; 2-pyridinyl; 3,4-methylenedioxyphenyl; butyl; 5-bromothiophen-2-yl; 5-methylthiophen-2-yl; 4- (trifluoromethoxy) phenyl; 3-phenoxyphenyl; 5-nitrothiophen-2-yl; 4-bromothiophen-2-yl; 3-methylthiophen-2-yl; furan-2-yl; furan-3-yl; 5-methylfuran-2-yl; 4- (2-propyl) phenyl; 3,4-dimethoxyphenyl; hexyl; 2-methyl-2-propyl; 4- (2-propyl) phenyl; 4-propylphenyl; 3-methoxyphenyl; 3-bromophenyl; 3-fluorophenyl; 3-trifluoromethylphenyl; 3-chlorophenyl; 3,5-dichlorophenyl; 3-methoxycarbonylphenyl; 3- (2-propyl) phenyl; 4- (2-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); (3-fluorophenyl) methyl; (4-bromophenyl) methyl; thiazole-2-yl; (3-methoxyphenyl) methyl; phenylmethyl; (3-methoxyphenyl) methyl; 4-methylphenyl; 4- (trifluoromethyl) phenyl; 4-ethylphenyl; acetamidophenyl; 4-phenoxy phenyl; 4-nitrophenyl; 4-fluorophenyl; 4-chlorophenyl; 4-aminophenyl; 4-methylthiophenyl; (4-phenyl) phenyl; (4-phenylmethoxy) phenyl; (4-N, N-diethylamino) phenyl; -2-phenylethenyl) phenyl; (2-methyl-2-propoxy) phenyl; 3-chlorophenyl; 3,5-dimethoxy phenyl; 4-N, N-dimethylphenyl; benzofuran-2-yl; 3-bromo-4-methoxyphenyl; 4-butoxy phenyl; 3-methoxyphenyl and 3,5-dichlorophenyl. The compound of claim 5, which 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) 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 [2,3d] pyrimidine; 4-amino-6- (4- (dimethylamino) phenyl) -7- (4-pyridinyl) pyrido [2,3d] 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 [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (thiophen-3-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (2-pyridinyl) pyrido [2,3-d] pyrimidine; 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 [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-bromothiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-methylthiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4- (trifluoromethoxy) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-phenoxyphenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-nitrothiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-bromothiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-methylthiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (furan-2-yl) pyrido [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (furan-3-yl) pyrido [2,3d] pyrimidine; 4-Amino-6- (4-methyl-phenyl) -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-nitrothiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (5-nitrothiophen-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-amino-6-hexyl-7- (4- (dimethylamino) phenyl) pyrido [2,3d] 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; 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 [2,3d] 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) pyrido [2,3-d] pyrimidine; 4-amino-6- (3-chlorophenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] 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 [2,3-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 [2,3d] pyrimidine; 4-amino-6- (3- (2-propyl) phenyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] 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 [2,3d] 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 [2,3d] 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 [2,3d] pyrimidine; 4-amino-6-butyl-7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine; 4-Amino-6-pentyl-7- (4- (dimethylamino) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (2-methylpropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine; 4-amino-6-propyl-7- (4- (dimethylamino) phenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (3-cyanopropyl) -7- (4- (dimethylamino) phenyl) pyrido [2,3d] 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 [2,3-d] pyrimidine; • · t · · · · · · · · · · · · · · · · · 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-methylphenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methoxyphenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-ethylphenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-cyanophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-acetamidophenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-phenoxyphenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-nitrophenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-fluorophenyl) pyrido [2,3d] pyrimidine; γχη 4-amino-6- (4-methylphenyl) -7- (4-chlorophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-aminophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-methylthiophenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7 - ((4-phenyl) phenyl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7 - ((4-phenylmethoxy) phenyl) pyrido [2,3d] 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 [2,3d] 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 [2,3d] 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-bromophenyl) -7- (4-N, N-dimethylaminophenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (3-bromo-4-methoxyphenyl) -7- (4-N, N-dimethylaminophenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (3-bromo-4-methoxyphenyl) -7- (thiophen-2-yl) pyrido [2,3-d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (4-butoxyphenyl) pyrido [2,3d] pyrimidine; 4-amino-6- (4-methylphenyl) -7- (3-methoxyphenyl) pyrido [2,3d] pyrimidine; and 4-Amino-6- (4-methylphenyl) -7- (3,5-dichlorophenyl) pyrido [2,3-d] pyrimidine. 11. A method of inhibiting adenosine kinase comprising exposing adenosine kinase to an effective inhibitory amount of a compound of claim 1 or claim 5. 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or claim 5 in combination with a pharmaceutically acceptable carrier. A method of treating ischemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal dysfunction, diabetes and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 or claim 3. 14. The method of claim 12, wherein the method comprises treating cerebral ischemia, myocardial ischemia, angina, coronary arterial bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, painful. perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility. A process for preparing a compound having the general formula 15 Dec (Π) wherein R and R are 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 4,6-diamino-5-iodopyrimidine ethenylboronové acid derivative having the general formula (HO) ₂ B ^ \ _{R 3} wherein R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl , arylalkyl or heterocyclic or heteroaryl or substituted versions thereof, in the presence of tetrakistriphenylphosphmpalladium (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 compound having the formula R ⁴ -CHO, wherein R ⁴ is an aryl, heteroaryl or heterocyclic group, or a substituted version thereof, under anhydrous conditions and removing water from the reaction, and isolating the compound of formula ( Π). 16. A process for preparing a compound having the general formula R ³ R ⁴ (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 another atom oxygen or nitrogen, with the requirement that both R and R are not hydrogen; R &^lt; 1 &gt; 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 a compound having the general formula H wherein R and R are 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; 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 the designation Y is selected from the group consisting of halide, methanesulfonate and ptoluenesulfonate; (ii) an arylalkylating agent of formula R ¹ -lower alkyl-Y, wherein R ¹ is arylalkyl and the designation Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate; (Iii) an acyl compound of formula R * -Z, wherein R ¹ is an acyl group and Z is selected from the group consisting of a portion of an acid anhydride, a halide, or an acyl activating group; and (b) optionally, if it is 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-Y, wherein: R is lower alkyl and Y is selected from the group consisting of halide, methanesulfonate, and toluenesulfonate; (ii) an arylalkylating agent of formula R-lower alkyl-Y, wherein R 'is arylalkyl and Y is selected from the group consisting of halide, methanesulfonate, and p-toluenesulfonate; (iii) an acyl compound of formula R-Z, wherein R is acyl and Z is selected from the group consisting of an acid anhydride, halide or acyl activating moiety; 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 and 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 and R 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 • · · « And (a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the general formula (HO) ₂ B ^^ _{R 3} where R ³ is lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, heterocyclo or heteroaryl or substituted versions thereof in the presence of tetrakistriphenylphosphine palladium (O) and aqueous alkali metal base, and isolating the first intermediate compound having the formula formula (b) reacting the first intermediate with an aldehyde of a compound having the formula R ⁴ -CHO, wherein the substituent R ⁴ is an aryl, heteroaryl or heterocyclic group, or a substituted version thereof, under anhydrous conditions and removing water from the reaction; and (c) reacting the fourth intermediate with an amine compound having the general formula R 1 -NH-R ² , wherein the substituents R ¹ and R ² are as described above, and isolating the compound of the formula e (II). 18. A compound of the formula: R ³ and R ⁴ are as defined above.