AU744528B2

AU744528B2 - 6,7-disubstituted-4-aminopyrido(2,3-d)pyrimidine compounds

Info

Publication number: AU744528B2
Application number: AU70981/98A
Authority: AU
Inventors: Shripad S. Bhagwat; Yu-Gui Gu; Chih-Hung Lee; Richard J. Perner
Original assignee: Abbott Laboratories
Current assignee: Abbott Laboratories
Priority date: 1997-04-16
Filing date: 1998-04-16
Publication date: 2002-02-28
Anticipated expiration: 2018-04-16
Also published as: IL131892A0; AR012435A1; EP0979230A1; NZ337844A; TW458977B; NO995033D0; SK142099A3; CN1259948A; BR9809088A; HUP0001402A2; KR20010006453A; AU7098198A; TR199902456T2; WO1998046603A1; HUP0001402A3; CA2287465A1; PL336262A1; JP2001520649A; BG103861A; NO995033L

Description

WO 98/46603 PCT/US98/04127 6,7-DISUBSTITUTED-4-AMINOPYRIDO[2,3-D1PYRIMIDINE COMPOUNDS Technical Field The present invention relates a method for inhibiting adenosine kinase by administering 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds, to pharmaceutical compositions containing such compounds, as well as novel 6,7disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.

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

Adenosine is a purine nucleoside that is an intermediate in the pathways of purine nucleotide degradation and salvage. Adenosine also has many important physiologic effects, many of which are mediated through the activation of specific ectocellular receptors, termed P1 receptors (Burnstock, in Cell Membrane Receptors for Drugs and Hormones, 1978, (Bolis and Straub, eds.) Raven, New York, pp. 107-118; Fredholm, et al., Pharmacol. Rev. 1994, 46: 143-156).

In the central nervous system, adenosine inhibits the release of certain neurotransmitters (Corradetti, et al., Eur. J. Pharmacol. 1984, 104: 19-26), stabilizes membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, 4: 346-360), functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci. 1986, 7: 128-130) and may have a role as an endogenous neuroprotective agent (Rudolphi, et al., Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine may play a role in several disorders of the central nervous system such as schizophrenia, anxiety, depression and Parkinson's disease. (Williams, in Psychopharmacology: The Fourth Generation of Progress; Bloom, Kupfer Raven Press, New York, 1995, pp 643-655.

Adenosine has also been implicated in modulating transmission in pain pathways in the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and in mediating the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther. 1987, 243: 657-665). In the immune system, adenosine inhibits certain neutrophil functions and exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-13). An AK WO 98/46603 PCTIS98/04127 inhibitor has been reported to decrease paw swelling in a model of adjuvant arthritis in rats (Firestein, et.al., Arthritis and Rheumatism, 1993, 36, S48.

Adenosine also exerts a variety of effects on the cardiovascular system, including vasodilation, impairment of atrioventricular conduction and endogenous cardioprotection in myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and Adenosine Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334). The widespread actions of adenosine also include effects on the renal, respiratory, gastrointestinal and reproductive systems, as well as on blood cells and adipocytes.

Adenosine, via its Al receptor activation on adipocytes, plays a role in diabetes by inhibiting lipolysis [Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551.

Endogenous adenosine release appears to have a role as a natural defense mechanism in various pathophysiologic conditions, including cerebral and myocardial ischemia, seizures, pain, inflammation and sepsis. While adenosine is normally present at low levels in the extracellular space, its release is locally enhanced at the site(s) of excessive cellular activity, trauma or metabolic stress. Once in the extracellular space, adenosine activates specific extracellular receptors to elicit a variety of responses which tend to restore cellular function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943; Miller and Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured in seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-C806), and its endogenous actions are therefore highly localized.

The inhibition of adenosine kinase can result in augmentation of the local adenosine concentrations at foci of tissue injury, further enhancing cytoprotection. This effect is likely to be most pronounced at tissue sites where trauma results in increased adenosine production, thereby minimizing systemic toxicities.

Pharmacologic compounds directed towards adenosine kinase inhibition provide potentially effective new therapies for disorders benefited by the site- and event-specific potentiation of adenosine. Disorders where such compounds may be useful include ischemic conditions such as cerebral ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA), stroke, other thrombotic and embolic conditions, and neurological disorders such as epilepsy, anxiety, schizophrenia, nociperception including pain perception, neuropathic pain, visceral pain, as well as inflammation, arthritis, immunosuppression, sepsis, diabetes and gastrointestinal disfunctions such as abnormal gastrointestinal motility.

A number of compounds have been reported to inhibit adenosine kinase. The most potent of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), 5-iodotubercidin (Wotring and Townsend, Cancer Res. 1979, 39: 3018- WO 98/46603 PCT/US98/04127 3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984, 33: 347- 355).

Adenosine kinase is also responsible for the activation of many pharmacologically active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345), including tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine riboside. These purine nucleoside analogs represent an important group of antimetabolites which possess cytotoxic, anticancer and antiviral properties. They serve as substrates for adenosine kinase and are phosphorylated by the enzyme to generate the active form. The loss of adenosine kinase activity has been implicated as a mechanism of cellular resistance to the pharmacological effects of these nucleoside analogs Bennett, et al., Mol. Pharmacol., 1966, 2: 432-443; Caldwell, et al., Can. J. Biochem., 1967, 45: 735-744; Suttle, et at., Europ. J. Cancer, 1981, 17: 43-5 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 the phosphorylation of 2'deoxyadenosine, has been suggested as a toxic mechanism in the immune defect associated with inheritable adenosine deaminase deficiency (Kredich and Hershfield, in The Metabolic Basis of Inherited Diseases, 1989 (Scriver, et al., eds.), McGraw-Hill, New York, pp.

1045-1075).

B.S. Huribert et al. Med. Chem_, 11 7 711-717 (1968)) disclose various 2,4diamidnopyrido[2,3-dlpyrimidine compounds having use as antibacterial agents. R. K.

Robins et al. Amer. Chem. Soc., 80:3449-3457 (1958)) disclose methods for preparing a number of 2,4-dihydroxy-, 2,4-diamnino-, 2-am-ino-4-hydroxy- and 2-mercapto-4hydroxypyrido[2,3-d]pyrimidines having antifolic acid activity. R. Sharma et al., (Indian J.

Chem., 31B: 7 19-720 (1992)) disclose 4-amidno-5-(4-chlorophenyl)-7-(4nitrophenyl)pyridoll2,3-d]pyrimidine and 4-amidno-5-(4-methoxyphenyl)-7-(4nitrophenyl)pyrido[2,3-d]pyrim-idine compounds having antibacterial activity. A. Gupta et al., Indian Chem. Soc., 635-636 (1994)) disclose 4- amino- 5- (4-fluorop henyl)-7- (4-fluorophenyl)pyrido[2,3-d]pyrimidine and 4-anmino-5-(4-chlorophenyl)-7-(4fluorophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity. L. Prakash et at., Pharmazie, 48: 22 1-222 (1993)) disclose 4-amino-5-phenyl-7-(4amninophenyl)pyridoll2,3-d]pyrimidine, 4-amino-5-phenyl-7 -(4-bromophenyl)pyrido[2,3dipyrimidine, 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-dlpyimidine compounds having antifungal activity. P. Victory et al., Tetrahedron, 51: 10253-10258 (1995.)) discloses the synthesis of 4-amino-S ,7 -diphenylpyrido[2,3-d]pyrimnidine compounds from acyclic precursors. Bridges et al.(PCT application WO 95/ 19774, published July 27, 1995) 4 disclose various bicyclic heteroaromatic compounds as having utility for inhibiting tyrosine kinase of epidermal growth factors.

Summary of the Invention The present invention provides for 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds having utility as adenosine kinase inhibitors.

In one aspect, the present invention provides novel compounds having the formula

R

1

NR

2

H

N H 1 N N 7 R 4

(I)

wherein Ri and R2 are independently H, lower alkyl, arylalkyl or acyl, or may be taken together with the nitrogen atom to which they are attached to form a 5-to-7 membered ring optionally containing an additional oxygen or nitrogen atom; R 3 and R 4 are independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or a heterocyclic group and the dashed lines indicate a double bond is optionally present.

The present invention also contemplates the pharmaceutically acceptable salts and amides of ii the compounds of Formula I, and the use thereof as provided below.

In another aspect, the present invention provides a method for inhibiting adenosine kinase by administering a compound of Formula In particular, the method of inhibiting adenosine kinase comprises exposing an adenosine kinase to an effective inhibiting amount of a compound of Formula I of the present invention. Where the adenosine kinase is located in vivo, the compound is administered to the organism.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I above in combination with a pharmaceutically acceptable carrier.

In still another aspect, the present invention provides a method of treating ischaemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal 25 dysfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.

In a preferred aspect, the present invention provides a method of treating cerebral ischaemia, myocardial ischaemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I of the present invention.

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

LibC/479393spec In another aspect, the present invention provides a process for the preparation of compounds of formula I Rl NR2

H

'N T R 4

(I)

wherein R 1 and R 2 are hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, or a heterocyclic group; R 4 is aryl, or a heterocyclic group; wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of F, CI, Br, I, cyano, carboxamide, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkyl)amino, N-loweralkyl-N-loweralkoxyamino, trifluoromethyl, and methoxymethyl; the process comprising reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula (HO)2B R3, wherein R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heterocyclic or heteroaryl or substituted version thereof, in the presence of tetrakistriphenylphosphinepalladium(O) and an aqueous alkali metal base, and isolating a first intermediate compound having the formula

NH

2

*N

S 15 NH 2 reacting the first intermediate compound with an aldehyde compound having the formula

R

4 -CHO, wherein R 4 is aryl, heteroaryl, or a heterocyclic group, under anhydrous conditions and with the removal of the water of reaction, and isolating the compound of formula I.

In another aspect, the present invention provides a process for the preparation of compounds 20 of formula I.

R NR 2

H

:4

H

R

3

R

4 l wherein R 1 and R 2 are independently H, loweralkyl, with the requirement that not both R 1 and R 2 may be hydrogen, R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or a heterocyclic group; R 4 is aryl or a heterocyclic group; wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of F, CI, Br, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkyl)amino, N-loweralkyl-Nloweralkoxyamino, trifluoromethyl, and methoxymethyl.

the process comprising LibC/479393spec A reacting a compound having the formula 2N N R 4 wherein R 1 and R 2 are hydrogen;

R

3 and R 4 are as defined above, with a compound selected from the group consisting of an alkylating agent R1-Y, wherein R 1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent RI-loweralkyl-Y, wherein R 1 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R 1 wherein R1 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired compound; and optionally, when it is desired that R 2 should not be hydrogen, treating the compound from step (a) with a compound selected from the group consisting of an alkylating agent R 2 wherein R 2 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; :i 1 (ii) an arylalkylating agent R 2 -loweralkyl-Y, wherein R 2 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R 2 wherein R 2 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired product.

In another aspect, the present invention provides a process for the preparation of compounds of formula I R R 2 R N,R2 H 1 20 wherein R 1 and R 2 are independently H, loweralkyl, with the proviso that not both R 1 and R 2 are hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, or a heterocyclic group; R 4 is aryl, or a heterocyclic group: wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of F, CI, Br, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkyl)amino, N-loweralkyl-Nloweralkoxyamino, trifluoromethyl, and methoxymethyl; the process comprising reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the (HO)2 3 formula (HO)2B R3, wherein R 3 is as defined above in the presence of tetrakistriphenylphosphinepalladium(0) and an aqueous alkali metal base, and isolating a first

CI

intermediate compound having the formula N NH2 reacting the first intermediate compound with an aldehyde compound having the formula /\ST R 4 -CHO, wherein R 4 is as defined above under anhydrous conditions and with the removal of the LibC/479393spec water of reaction, and isolating the second intermediate compound having the formula cl

SR

4 and treating the fourth intermediate compound with an amine compound having the formula

R

1

-NH-R

2 wherein R 1 and R 2 are as described above, and isolating the desired product.

Detailed Description of the Invention The present invention relates to 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds that are useful in inhibiting adenosine kinase, to pharmaceutical compositions containing such compounds, to a method of using such compounds for inhibiting adenosine kinase, and to novel 6,7disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.

In one aspect, the present invention provides 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds that are adenosine kinase inhibitors. An adenosine kinase inhibitor of the present invention is a compound of the Formula I or II, shown above.

In a preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula or (II) above, wherein R 4 is aryl or heteroaryl and substituted versions 15 thereof.

In a more preferred embodiment, an adenosine kinase inhibitor of the present invention is a compound of Formula above, wherein Ri and R2 are hydrogen; R3 is selected from the group consisting of alkyl, aryl, and arylalkyl; and R4 is aryl; wherein, for the foregoing R 3 the aryl and aryl part of the arylalkyl are unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, dialkylamino, F, CI, Br, trifluoromethyl, and methylenedioxy; and wherein, for the foregoing R 4 the aryl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, cyano, amino, dialkylamino, halo, trifluoromethyl, and methylenedioxy.

In an additional embodiment, the present invention relates to compounds of formula I as shown 25 above wherein R 3 is selected from the group consisting of 3-bromo-4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 4-butoxyphenyl, butyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3,4dimethoxyphenyl, 4-(1,1-dimethylethyl)phenyl, 4-(dimethylamino)phenyl, 3-fluoro-4-methylphenyl, 3fluorophenyl, 4-fluorophenyl, hexyl, 3-methoxyphenyl, 4-methoxyphenyl, (3-methoxyphenyl)methyl, (4methoxyphenyl)methyl, 3,4-methylenedioxyphenyl, 4-methylphenyl, 2-methylpropyl, pentyl, 2phenylethyl, phenylmethyl, 3-phenylpropyl, propyl, 4-propylphenyl, 3-(2-propyl)phenyl, 4-(2propyl)phenyl, and 3-trifluoromethylphenyl.

The invention also relates to compounds wherein R 4 is selected from the group consisting of (4aminophenyl), (4-bromophenyl), (3-chlorophenyl), (4-chlorophenyl), (4-cyanophenyl), dichlorophenyl, (4-(diethylamino)phenyl), (3,5-dimethoxyphenyl), (4-(dimethylamino)phenyl), (4ethylphenyl), (4-fluorophenyl), (3-methoxyphenyl), (4-methoxyphenyl), (4-methylphenyl), (3,4methylenedioxyphenyl), phenyl, 4-(2-propyl)phenyl, (4-(tert-butoxy)phenyl), and 4- S*,T uoromethyl)phenyl.

T- Exemplary and preferred compounds of the invention include: LibC/479393spec 4-amino-6-phenyl-7-(p-dimethylaminophenyl)pyrido[2,3-dlpyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[23-dlpyrimidine; 4-am ino-6-(4-(d imethylamino) phenyl)-7-(4-(d imethylamin o) phenyl)pyrido[2,3-d]pyri mid ine; 4-amino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidime; 4-amino-6-(4-methylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[23-d]pyrimidine; 4-ami no-6-(4-methyl phenyl)-7-(4-(5-pyri mid inyl)phenyl) pyrido[2, 3-d]pyri mid ine; 4-amino-6-(4-methyl phenyl)-7-(3-pyrid inyl) pyrido[2, 3-dlpyri mid m e; 4-amino-6-(4-methylphenyl)-7-(thiophen-3-y)pyrido[2,3-d] pyrimidine; 4-amino-6-(4-methylphenyl)-7-(thiophen-2-y)pyrido[2,3-d] pyrimidine; 4-am ino-6-(4-methylpheny)-7-(2-pyrid inyl) pyrido[2, 3-dipyri mid ine; 4-amino-6-(4-methyiphenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-butyl-7-(thiophen-2-y)pyrido[2,3-d]pyrimidine; 4-amino-6-butyl-7-(thiophen-3-y)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(5-bromothiophen-2-y)pyrido[2, 3-dipyrimidine; 4-mn--4m typey)7(-ehltipe-*lprd [,-~yiiie 4-amino-6-(4-methylphenyl)-7-(5-methylthiophen-2-y)pyrido[2, 3-dipyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-bromothiophen-2-y)pyrido[2, 3-dipyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-etylhphn-2-yI)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(furan--yI)pyridot2,3-dlpyrimidine; 4-amino-6-(4-methyphenyl)-7-(u-3eh-Ia2y)pyrido[2, -d pyrimidine; 4-ami no-6-(4-methroylphenyl)-7-(mthyl-furn-2-y) pyrido[2,3-d]pyri mid ine; 4-amino-6-(4-(2-propylan)phenyl)-7-(thiophen-2-y)pyrido[2,3-dlpyrimidine; 254-amino-6-(34-dimethyiphenyl)-7-(thiophen2yl)pyrido[23d]pyrimidine; 25 4-ami no-6-(3,l-4-dmethmehyl)-7(i ophen-yI)pyrido[2,3-d]pyri mid e; 4-amino-6-hexyl-7-(4-(impeth2ylm)peylpyrido[3-pyrimidine; 0. 0: 4-amino-6-hexeyl2rpl-7-(thiophen-2-y)pyrido[2,3-d]pyrimidine; 4-amino-6-(42-ethylpopyl)-7-(hiph2yaino)pyrido[2,3-d]pyrimidine; 304-amino-6-(4-(2propylphenyl)-7-(4-dimethyamino)phenyl)pyrido[2,3-d]pyrimidine; 304-amino-6-(34-proyphenyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-6-(3-methoxyphenyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-am ino-6-(3-rmoxphenyl)-7-(4-d imethylani no)phenyl) pyrido[23-dpyri mid ine; 4-amino-6-(3-bromrophenyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-am ino-6-(3-tfluoromhlphenyl)-7-(4-dhlmeto~hylmn) phyl)[2pyrimi[23d] in mi n 4-amino-6-(3-triloromyphenyI)-7-(4-dimethy arnino)pheny)pydo[2,3-d]pyrimidine; 4-amino-6-(3,-chlorophenyl)-7-(4-d imethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3,5-dichlroxphenyl)-7-(4-dimethylamino)phenyl)pyrido[23-dlpyrimidine; 4-amino-6-(3,4-methylenedioxyphenyl)-7-(4-dimpehlno-hyl)pyrido[2,3-d]pyrimidine; S TS 4-amino-6-(3-methoxycarbonylphenyl)-7-(4-dimethylamino)phenyl)pyrido[23-d]pyrimidine; LibC/479393spec 9 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-(d imethyl amino) phenyl)pyrido[2,3-d]pyrimid ine; 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-dpyrimidine; 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-(d imethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-fluoro-4-methylphenyl)-7-(thiophen-2-y)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-am ino-6-(2-phenylethyl)-7-(4-d imethyl am ino)phenyl) pyrido[2,3-d]pyri mid ine; 4-amino-6-(2-phenylmethyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-butyl-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-pentyl-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(2-methylpropyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-am ino-6-propyl-7-(4-d imethylamino)pheny) pyrido[2,3-d] pyri mid ine; 4-amino-6-(3-cyanopropyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-pentyl-7-(thiophen-2-y)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-carboxamidopropyl)-7-(4-(dimethylamino)phenyl)pyrido2,3-d]pyrimidine; 20 *-mn (-ehxpey~ ehl--tipe--lprd yiiie 20 4-amino-6-((4-rmetoxphenyl)methyl)-7-(thiophen-2-y)pyrido[2,3-d]pyrimidine; 4-amino-6-((4-b2-roophenyl)methyl)-7-(thiophen-2-y)pyrido[2,3-d]pyrimidine; 4-amino-6-((4-(2-propyphenyl)methyl)-7-(thi-olpheny)pyrido[2,3-d]pyrimidine; ~4-amino-6-((4-rmetophenyl)methyl)-7-(4ho-(2-pipyl)pyrido[2,3-dpyrimidine; 4-amino-6-((4-bromrophenyl)methyl)-7-(thiophen-2-yI)pyrido[2,3-djpyrimidine; 5 4-amino-6-((3-flurophenyl)methyl)-7-(thioe-2-y)pyrido[2,3-dpyrimidine; 4-amino-6-((4-rmtoxphenyl)methyl)-7-(thioen-2-yI)pyrido[23-d]pyrimidine; 4-am ino-6-((-exphenylmethyl)-7-(th iophen-2-yI)pyrido[2,3-d] pyri mid me; *...4-amino-6-(phenmethxpyl)thhen--pyido[etdhymidiphne;prd[23dpriii 3o4-amino-6-((3-methoyphenyltyl)-7-(4-diflormethylan)phenyl)pyrido[23-d]pyrimidine; 4-amino-6-(4-methylpheny)-7-(4-rifluoromethy)phyidpyi2,3-d]pyr idine 4-amino-6-(4-methylphenyl)-7-(4-methyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-ethyphenyl)pyrido[2,3-dpyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-etylnphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-caophenyl)pyrido[2 ,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-acetamophenyl)pyrido23-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-lorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-minleoyphenyl)pyrido[2,3-d]pyrimidine; S T 4-am ino-6-(4-m ethy lpheny pheN di meth oxyi)phenyI)pyrido[2 3d]pyrim id ne; A LibC/479393spec S$9 F' 4-amino-6-(4-methylphenyl)-7-((4-2-phenylethenyl)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(2-methyl-2-propoxy)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyido[2,3-d]pyimidine; 4-ami no-6-(th iophen-2-yl)-7-(4-N, N-d imethylam inophenyl)pyrido[2,3-d]pyri mid ine; 4-amino-6-(4-methylphenyl)-7-(benzofuran-2-y)pyrido[2,3-d]pyrimidine; 4-amino-6-(thiophen-2-y)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-am ino-6-(th iophen-2-yl)-7-(4-methoxyphenyl) pyrido pyri mid ine; 4-amino-6-(bromophenyl)-7-(4-N ,N-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(4-N ,N-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-methoxyphenyl)pyrido [2,3-d]pyri mid ine; and 4-amino-6-(4-methylphenyl)-7-(3,5-d ich lorophenyl)pyrido[2,3-d] pyri mid ine; The term "aryl"~ or "substituted aryl", as used herein, refers to a carboxylic aromatic radical, including, for example, phenyl and 1- or 2-naphthyl, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, 1, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, 20 di(loweralkylamino), N-loweralkyl-N-loweralkoxyamino, trifluoromethyl or methoxymethyl groups. In addition, the term "aryl" refers to a phenyl group substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl, pyridazinyl, morpholinyl, phenyl-loweralkoxy, phenyl-loweralkenyl or cycloalkylloweralkyl group. Examples of aryl radicals include, but are not limited to, 3-bromophenyl, 3chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-propyl)phenyl, 3,4-dimethoxyphenyl, 3trifluoromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-methyl-N-methoxy)ethylaminophenyl, 4- 25 dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4-methylphenyl, 4-cyanophenyl, 4-propylmethyl, dichlorophenyl, 3,4-methylenedioxyphenyl, 3-cyanopropyiphenyl, 4-ureidophenyl, 3methylsulfonylphenyl, 3-carboxamidopropyiphenyl or others as shown herein.

The term "arylalkyl" refers to a loweralkyl radical having appended thereto an aryl group, as defined above, as for example benzyl and phenylethyl.

The term "aryloxy" refers to a aryl radical which is appended to the molecule via an ether linkage through an oxygen atom), as for example phenoxy, naphthyloxy, 4-chlorophenoxy, 4methyiphenoxy, 3,5-dimethoxyphenoxy, and the like.

The term "cycloalkyl' refers to a cyclic saturated hydrocarbon radical having from 3 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is also described as C 3 -CBcycloalkyl.

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

A LibC/479393spec 11 The term "heterocyclic" refers to a saturated or unsaturated monocyclic ring system radical having from four to seven ring atoms of which one is nitrogen or oxygen; one or two ring atoms are additional heteroatoms independently selected from S, 0 and N; and the remainder are carbon, the radical being joined to the rest of the molecule via any of the ring atoms and being optionally substituted, either on a nitrogen or a carbon atom, by an additional radical selected from among aryl(loweralkyl), alkoxycarbonyl, loweralkyl, halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy, loweralkoxy, halogen, amino, loweralkylamino, and amino, (loweralkyl)amino or alkanoylamino of from one to eight carbon atoms in which the amino group may be further substituted with alkanoyl of from one to eight carbons, an a-amino acid or a polypeptide. Examples of heterocyclic include pyrrolidine, tetrahydrofuran, dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, aziridine and azetidine and those additionally described herein.

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

The term "loweralkyl", as used herein, refers to saturated, straight- or branched-chain S hydrocarbon radicals containing from one to six carbon atoms including, which may be unsubstituted or substituted by independent replacement of one, two or three of the hydrogen atoms thereof with CI, 2 Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy, amino, loweralkylamino, di(loweralkylamino) or N- 20 loweralkyl-N-loweralkoxyamino groups. Examples of loweralkyl include, but are not limited to, methyl, S"ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, hydroxyethyl, methoxymethyl, trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, and the like. In certain cases, the group "Ci- C6alkyl" is described and has a similar meaning as above for loweralkyl but is more specifically recited. Likewise, the term "Co-Csalkyl" indicates the carbon atoms which may be present in the alkyl 25 chain including zero. These terms are also provided adjacent to aryl or heteroaryl or other generic group and represent or have the same meaning as, for example, "arylalkyl" or "heteroarylalkyl".

The term "loweralkenyl", as used herein, refers to mono-unsaturated straight- or branchedchain hydrocarbon radicals containing from two to six carbon atoms including, but not limited to, vinyl, propenyl, n-butenyl, i-butenyl, n-pentenyl, and n-hexenyl. These variables are also recited as, for example, C2-C6alkenyl.

The term "loweralkoxy" refers to a loweralkyl radical which is appended to the molecule via an ether linkage through an oxygen atom), as for example methoxy, ethoxy, propoxy, 2-propoxy, 2methyl-2-propoxy, tert-butoxy, pentyloxy, hexyloxy, isomeric forms thereof and the like. This term is also described as C1-Csalkyloxy.

The term "loweralkynyl", as used herein, refers to straight- or branched-chain hydrocarbon radicals possessing a single triple bond and containing from two to six carbon atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl, and n-hexynyl. This term is also described as C2- Csalkynyl.

The term "mammal" has its ordinary meaning and includes human beings.

OC ^LibC/479393spec si0i° 12 In a further aspect of the present invention pharmaceutical compositions are disclosed which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.

The present invention includes one or more compounds, as set forth above, formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.

As is well known in the art, a compound of the present invention can exist in a variety of forms including pharmaceutically-acceptable salts, amides and the like.

Compositions may be prepared that will deliver the correct amount of a compound or compounds of the invention. The following dosages are thought to provide the optimal therapy: iv infusions: 0.1-250nmol/kg/minute, preferably from 1-50nmol/kg/minute; oral: 0.01-250pMollkg/day, preferably from about 0.1-50pMol/kg/day; these oral molar dosage ranges correspond to 0.005- 125mg/kg/day, preferably 0.05-25mg/kg/day. For treatment of acute disorders the preferred route of administration is intravenous; the preferred method of treating chronic disorders is orally by means of a tablet or sustained release formulation.

"Pharmaceutically-acceptable amide" refers to the pharmaceutically-acceptable, nontoxic amides of the compounds of the present invention which include amides formed with suitable organic acids or with amino acids, including short peptides consisting of from 1-to-6 amino acids joined by S 20 amide linkages which may be branched or linear, wherein the amino acids are selected independently Sfrom naturally-occurring amino acids, such as for example, glycine, alanine, leucine, valine, phenylalanine, proline, methionine, tryptophan, asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine, lysine, arginine, tyrosine, histidine, ornithine, and the like.

"Pharmaceutically-acceptable salts" refers to the pharmaceutically-acceptable, nontoxic, *e 25 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 heterocyclic which have substituents around the aryl, heteroaryl, heterocyclic or other genera variable at chemically appropriate positions and as designated or exemplified herein.

The compounds of the present invention can be used in the form of pharmaceuticallyacceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, flavinate, fumarate, glucoheptanate, glycerophosphate, hemisulfate, heptanate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

-ST Fc Appropriate cationic salts are also readily prepared by conventional procedures such as trFeating an acid of Formula I with an appropriate amount of base, such as an alkali or alkaline earth 0 LibC/479393spec metal hydroxide, eg., sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, eg., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. Also, the basic nitrogen-containing groups can be quaternised with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides, and others.

Water or oil-soluble or dispersible products are thereby obtained.

The salts of the present invention can be synthesised from the compounds of Formula I or II which contain a basic or acidic moiety by conventional methods, such as by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt forming inorganic acid or base in a suitable solvent or various combinations of solvents.

Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers compositions, in the manner described below.

Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for 20 reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

S.. 25 These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds may be incorporated into slowrelease or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilised, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilising agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fT fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) inders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and LibC/479393spec 14 acacia; humectants, as for example, glycerol; disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; solution retarders, as for example paraffin; absorption accelerators, as for example, quaternary ammonium compounds; wetting agents, as for example, cetyl alcohol and glycerol monostearate; adsorbents, as for example, kaolin and bentonite; and lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such a tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, S 20 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, solubilising agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil 25 and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavouring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical or transdermal administration of a compound of this invention further STo include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred LibC/479393spec kvov( Ic dosage form of the present invention. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with absorption-retarding agents or baniers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The present compounds may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.

Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilisers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. (1976), p 33 et seq.

Synthetic Methods The compounds and processes of the invention will be better understood in connection with the 20 following synthetic Schemes I and 2 which illustrate the methods by which the compounds of the invention may be prepared. The groups R 1

R

2

R

3 and R 4 are defined above unless otherwise noted.

Scheme 1

NH

2

NH

2

NH

2

NH

2 f IR 3 R 3 R R 3 N NH1+ (HO R 2 3: NH 2 3+0 R 4 4- N In accordance with Scheme 1 are prepared compounds of Formula (II) wherein R 1 and R 2 are hydrogen. A starting material, 4,6-diamino-5-iodopyrimidine is reacted with ethenylboronic acid derivatives wherein R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or, heterocyclic or substituted versions thereof, to prepare compound in the presence of tetrakistriphenylphosphinepalladium(0) or other suitable palladium(O) complexes, and aqueous alkali metal base, such as sodium or potassium hydroxide, for example, preferably buffered with an aqueous sodium or potassium bicarbonate at reflux for about 8 to about 24 hours. Compound may be prepared from 4,6-diaminopyridine by treatment with iodine in DMF at about 40 0 C to about for about 24 hours in the presence of potassium carbonate. Compounds of formula may be prepared by reaction of an R 3 -substituted acetylene with catecholborane in a solvent such as THF. R 3 substituted acetylenes may be prepared according to various literature procedures, such as, for example, Van Hijfte et al., Tetrahedron Letters, 1989, 30; 3655; Tao et al., J. Org.Chem., 1990, 63; and Rossi et al., Gazz. Chim. Ital., 1990, 120: 783-791.

Compound is then reacted with the aldehyde compound wherein R 4 is aryl, heteroaryl, R< or a heterocyclic group, to prepare compound in a suitable anhydrous solvent, under Suzuki LibC/479393spec

;ST

03 16 reaction conditions, such as diphenyl ether, 1,2,4-trichlorobenzene, toluene, or the like, in the presence of 4A molecular sieves to adsorb the water of reaction, at reflux for from about 2 to about 24 hours. Compounds are compounds of Formula (II) wherein R 1 and R 2 are hydrogen. The compounds prepared according to Scheme 1 may be further treated with a suitable reducing agent such as hydrogen in the presence of a catalyst or other reducing agent to form the 5,6 and/or 7,8 reduced versions of a compound of formula II. In addition, reduction can proceed to form single bonds at the 5,6 and 7,8 positions and a double bond between the 6, 7 carbons. In the former case(s), stereoisomers are formed and are included within the scope of the invention. These isomers may be isolated by conventional means.

Scheme 2

R

1

R

2

NH

2

NR

N 3R 3 N N R 5 N N R 4 6 In accordance with Scheme 2, compounds of Formula (II) wherein one or both of R 1 and R 2 are loweralkyl, may be prepared by treatment of compound with the appropriate reagent. To prepare compounds of formula wherein R 1 and R 2 are not both hydrogen atoms, it is possible to prepared 15 the desired derivative from the compound of Formula wherein R 1 and H.

2 are both hydrogen atoms.

When R 1 or R 2 is loweralkyl this may be accomplished by reaction of the free amino group with the appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the presence of a base such as triethylamine or potassium carbonate in a suitable solvent, such as for example, methylene chloride or THF. Also, this alternate procedure may be used to prepare alkyl substituted amino compounds, for example by reacting the chloro compound with a mono- or disubstituted amine, such as for example, diethylamine, dibutylamine. This reaction takes place readily in a solvent such as methylene chloride, for example, in the presence of a tertiary amine.

The precursor compound having a halogen atom in place of the amino group at the 4-position may be prepared by substitution of 6-amino-4-chloro-5-iodopyrimidine for the 4,6-diamino-5-iodopyrimidine 25 (compound of Scheme I) and carrying the product forward.

Method of Inhibiting Kinase In yet another aspect of the present invention a method of inhibiting adenosine kinase is disclosed. In accordance with this method, an adenosine kinase enzyme is exposed to an effective inhibiting amount of an adenosine kinase inhibitor compound of the present invention. Preferred such compounds for use in the method are the same as set forth above. Means for determining an effective inhibiting amount are well known in the art.

The adenosine kinase to be inhibited can be located in vitro, in situ or in vivo. Where the adenosine kinase is located in vitro, adenosine kinase is contacted with the inhibitor compound, typically by adding the compound to an aqueous solution containing the enzyme, radiolabelled substrate adenosine, magnesium chloride and ATP. The enzyme can exist in intact cells or in isolated subcellular fractions containing the enzyme. The enzyme is then maintained in the presence of the Sinhibitor for a period of time and under suitable physiological conditions. Means for determining ST /maintenance times are well known in the art and depend inter alia on the concentrations of enzyme SLibC/479393spec N 17 and the physiological conditions. Suitable physiological conditions are those necessary to maintain adenosine kinase viability and include temperature, acidity, tonicity and the like. Inhibition of adenosine kinase can be performed, by example, according to standard procedures well known in the art (Yamada, et al., Comp. Biochem. Physiol. 1982, 71 B: 367-372).

Where the adenosine kinase is located in situ or in vivo, is typically administered to a fluid perfusing the tissue containing the enzyme. That fluid can be a naturally occurring fluid such as blood or plasma or an artificial fluid such as saline, Ringer's solution and the like. A process of inhibiting adenosine kinase in vivo is particularly useful in mammals such as humans. Administering an inhibitor compound is typically accomplished by the parenteral intravenous injection or oral) administration of the compound. The amount administered is an effective inhibiting or therapeutic amount.

By a "therapeutically-effective amount" of the compound of the invention is meant a. sufficient amount of the compound to treat or mitigate adenosine kinase related disorders or those diseases or conditions which are ameliorated by adenosine kinase inhibition and elevated levels of adenosine, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is to be decided by the attending physician within the scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; 20 the specific composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with specific compound employed; and the like factors well known in the medical arts and well within the capabilities of attending physicians.

25 Compounds of the present invention inhibit adenosine kinase activity in vitro and in vivo. In vitro adenosine kinase activity can be measured using any of the standard procedures well known in the art. By way of example, cells containing adenosine kinase, such as IMR-32 human neuroblastoma cells, are cultured in the presence and absence of an inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of endogenous or externally applied 14 C-adenosine by these cells. The cells can be intact or broken. The specificity of adenosine kinase inhibitory activity is determined by studying the effects of inhibitors on adenosine Al and A2ct receptor binding, adenosine deaminase activity and adenosine transport.

Compounds of the present invention are effective in inhibiting adenosine kinase activity in vivo.

Numerous animal models for studying adenosine kinase activity and the affects of inhibiting such activity are well known in the art. By way of example, adenosine kinase inhibitors have been reported to protect rodents mice and rats) from seizures induced by the subcutaneous administration of pentylenetetrazol (PTZ). Typically the rodents are injected with various doses of a given inhibitor followed at various times by the subcutaneous administration of from about 10 to about 500mg/kg of STPTZ. The injected animals are then observed for the Onset of seizures.

OF\ LibC/479393spec 18 The compounds of the invention were tested in vivo in the hot plate test of analgesia in mammals such as mice. For example, the compounds of examples 55, 103 and 104 in the procedure described directly below were tested thirty minutes after pretreatment with the drugs (30pmol/kg i.p.) for latency to 10 th jump (in seconds). The longer the number of seconds, the more effective the drug at masking the pain felt from the hot plate. Compound 55 resulted in 132.86s relative to the vehicle alone of 72.76±10.51s. Compound 103 resulted in 103.29s. Compound 104, when tested, resulted in an insignificant score of 62.44s and will be retested in additional models of pain. Compounds of the invention are therefore potent pain relievers as well as adenosine kinase inhibitors as demonstrated in this animal model and the additional assays described below.

Mouse Hot Plate Assay Male CF1 mice (Charles River) of approximately 25-30g body weight are pretreated with of the test compounds, i.p. or p.o, in groups of 8 animals per dose. At the end of the pretreatment period, the mice are placed in an Omnitech Electronics Automated 16 Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in individual, 9.8x7.2x15.3cm (Ixwxh) plastic enclosures on top of a copper plate warmed to 55°C. Infrared sensors located near the top of each enclosure record beam crossings that occur as the mice jump off of the heated surface. Latency times for each jump are automatically recorded, and latency to both the first and tenth jumps are used for data analysis. Mice that do not reach the criteria of 10 jumps by 180s are immediately removed from the hotplate to avoid tissue damage, and they are assigned the maximum value of 180s as their 20 latency to tenth jump.

Numerous other animal models of adenosine kinase activity have been described [See, eg., 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 were tested in vitro and found to inhibit 25 adenosine kinase activity. The results of some representative studies are shown below in Table 1 below. The data indicate that the compounds inhibit adenosine kinase.

Table I of enttive Comound of th Invntio Inhibition of Adenosine Kinase by Representative Compounds of the Invention se**: 0 Compound of Example No. IC 5 o(nM) 2 73 3 185 6 467 9 317 14 11 29 250 31 48 52 117 54 200 69 33 91 8 LibC/479393spec 19 Method of Treating Cerebral Ischaemia, Epilepsy, Nociperception (Nociception) (Pain), Inflammation including conditions such as Septic Shock due to Sepsis Infection In yet another aspect of the present invention a method of treating cerebral ischaemia, epilepsy, nociperception or nociception, pain, inflammation including conditions such as septic shock due to sepsis infection in a human or lower mammal is disclosed, comprising administering to the mammal a therapeutically effective amount of a compound.

Alterations in cellular adenosine kinase activity have been observed in certain disorders.

Adenosine kinase activity was found to be decreased, relative to normal liver, in a variety of rat hepatomas: activity of the enzyme giving a negative correlation with tumour growth rate (Jackson, et al., Br. J. Cancer, 1978, 37: 701-713). Adenosine kinase activity was also diminished in regenerating liver after partial heparectomy in experimental animals (Jackson, et Br. J. Cancer, 1978. 37: 701- 713). Erythrocyte Adenosine kinase activity was found to be diminished in patients with gout (Nishizawa, et al., Clin. Chim. Acta 1976, 67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients infected with the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and increased in asymptomatic HIV-seropositive and HIV-seronegative high-risk subjects, S compared to normal healthy controls (Renouf, et al., Clin. Chem. 1989. 35: 1478-1481). It has been Ssuggested that measurement of adenosine kinase activity may prove useful in monitoring the clinical progress of patients with HIV infection (Renouf, et al., Clin. Chem. 1989, 35: 1478-1481). Sepsis infection may lead to a systemic inflammatory syndrome (SIRS), characterised by an increase in 20 cytokine production, neutrophil accumulation, haemodynamic effects, and tissue damage or death.

The ability of adenosine kinase inhibitor to elevate adenosine levels in tissues has been demonstrated to ameliorate syndrome symptoms, due to the know anti-inflammatory effects of adenosine. (Firestein, et al., J. of Immunology, 1994, pp. 5853-5859). The ability of adenosine kinase inhibitors to elevate adenosine levels is expected to alleviate pain states, since it has been demonstrated that administration of adenosine or its analogues results in antinociception or antinociperception.

(Swaynok, et al., Neuroscience, 1989, 32: No. 3, pp. 557-569).

The compounds and processes of the present invention will be better understood in connection with the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

Example 1 4-amino-6-phenyl-7-(p-dimethylaminophenyl)pyrido[2,3-dlpyrimidine A sample of 4,6-diamino-5-(2-phenylethenyl)pyrimidine (150mg) was suspended in 10mL of phenylether with 1.2eq of 4-(dimethylamino)benzaldehyde (the "R 4 Reagent) and 1.5g of 4A molecular sieves. The solution was heated to 170"C for 4h, then cooled, and the solvent was removed. The residue was purified by column chromatography to give the title compound. IR (KBr) 3325, 1589,1555,1400,1340,1196, 819 cm- 1 MS m/z 342 The 4,6-diamino-5-(2-phenylethenyl)pyrimidine was prepared as follows: la. 5-iodo-4.6-diaminopyrimidine 4,6-Diaminopyrimidine hemisulfate monohydrate (26.13g, 147.5mmol, Aldrich) and K 2 CO3 (30.58g, 221.3mmol) were suspended in water (400mL). To this suspension was added a solution of ijne (41.19g, 162.3mmol) in DMF (100mL). The mixture was heated at 45°C for 23h. After cooling, LibC/479393spec a 2M solution of Na 2 S20 3 (15mL) was added to quench the excess iodine. The white product was then collected, washed with water (3 x 20mL) and dried under high vacuum to yield 33.1g of the title compound lb. 2-phenylethenylboronic acid (the 'R 3 Reagent) Phenylacetylene (5mmol, Aldrich) was dissolved in 5mL of dry THF and catecholborane 1M in THF, Aldrich) was added dropwise at 0°C. The solution was heated to reflux for 1.5h, and the solvent was removed under vacuum. The solution was quenched with 1M HCI (10mL), and this solution is taken directly to the next step.

1c. 4,6-diamino-5-(2-phenylethenyl)pyrimidine To a solution of 5-iodo-4,6-diaminopyriniidine (1mmol, from step la above) in 50mL of dioxane, 2-phenylethenylboronic acid (5mmol), 5% of Pd(PPh3) 4 and 1M Na2CO3 (10mL) were added. The reaction mixture was heated for 12h. The solvent was removed under vacuum, and the residue was diluted with water and extracted with CH 2 CI2 (3 x 30mL). The organic layer was concentrated under reduced pressure, and the residue was dried under high vacuum. The crude mixture was subjected to column chromatography (using 5% MeOH/CH 2

CI

2 as eluant) to give the title compound. MS m/z: 213 M: Examples 2-107 Following the procedures of Example 1, except substituting the reagents given in Table 1 below for the R 4 and R 3 Reagents of Example 1, the compounds of Examples 2-107 were prepared.

o *o~o

P;

LibC/479393spec

IC,

-ci ~1

A

C. 0 0* 000 *0 0 0* 0 0 0 -0 0 **000 0 0 00 0 0 *0 00 0000 Table 1 Examples 2-107 Ex. IName R 4 Reagent-(7 position) R 3 Reagent-(6-position) Data No.

2 14-amino-6-(4-methylphenyl)-7-(4- 4-dimethylamino)-benzaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR (KBr) 3360, 1660, 1600, 1185, cm- 1 MS m/z 356 (dimethylamino)phenyl)pyridol2,3-dlpyrimidine 3 14-amino-6-(4-(dimethyiamino)pheny)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-dimethylaminophenyl)-etheny- IR (microscope) 3325, 1608, 1589, 1560, 1520, 1400, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine boronic acid 1358, 1340, 1196, 818 cm- 1 MS m/z 385 4 4-amino-6-(4-methylphenyl)-7-phenylpyndo[2,3-d]pyimidine Benzaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR (microscope) acid 3325, 1659, 1553, 1340, 1340, 821 cm- 1 MS m/z 313 4-amino-6-(methylphenyl)-7-(4-bromophenyl)pyrido[2,3- 4-bromobenzaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR (microscope) 3325, 1600, 1553, 1340, 1340, 818 dipyrimidine acid cm- 1 MS mlz 391 6 4-amino-6-(4-(dimethylamino)phenyl)-7-(4- Pyridine-4-carboxaldehyde 2-(4-dimethytaminophenyl)-ethenyl- IR (microscope) pyridinyl)pyrido[2,3-djpyrimidine boronic acid 3320, 1608, 1560, 1521, 1410, 1344, 818 MS mlz 343 MH~ 7 4-amino-6-(4-(dimethylamino)phenyl)-7-(4- 4-bromobenzaldehyde 2-(4-dimethylaminophenyl)-ethenyl- IR (microscope) 3320, 1606, 1562, 1547, 1520, 1340, bromophenyl)pyridof2,3-djpyrimidine boronic acid 1010, 818 cm- 1 MS m/z 420 [M+H1.

8 4-amino-6-(4-methylphenyl)-7-(4-(5- 4-(5-pyrimidinyl)benzaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3360, 3160, 1600, 1555, 1410, 1345, 820; MS mlz pyrimidinyl)phenyl)pyrido[2,3-dlpyrimidine acid 391 9 4-amino-6-(4-methylpheny)-7-(3-pyidiny)pyrido[2,3- 3-pyridinecarboxaldehyde 2-(4-methylphenyl).ethenyl-boronic IR 3320, 3360, 3040, 1640, 1550, 1340, 815; MS m/z dipyrimidine acid 34( 4-amino-6-(4-methylphenyl)-7-(thiophen-3-y)pyrido[2,3- 3-thiophenecarboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3440, 3320, 3160, 3100, 1600, 1555, 1335; MS dipyrimidine acid m/lz 319 I1I 4-amino-6-(4-methylphenyl)-7-(thiophen-2-y)pyrido[2,3- 2-thiophenecarboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3460, 3360, 3310, 3100, 1600, 1555, 1425; MS dipyrimidine acid mlz 319 12 4-amino-6-(4-methylphenyl)-7-(2-pyidinyl)pyrido[2,3- 2-pyridinecarboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3440, 3320, 3170, 1640, 1600, 1555, 1340; MS dipyrimidine acid m/z 314 13 4-amino-6-(4-methylphenyl)-7-(3,4- 3,4-methylenedioxybenzaidehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3365, 3120, 1600, 1555, 1440, 1250, 1040; MS meth ylenedioxyphenyl)pyrido[2,3-d]pyri mid ine acid m/z 357 14 4-amino-6-butyl-7-(thiophen-2-y)pyrido[2,3-d]pyrimidine 2-thiophenecarboxaldehyde 1-hexenyl-boronic acid IR 3320, 3160, 2955, 2860, 1640, 1560, 1335, MS /z 85 )H) 4-amino-6-buty-7-(thiophen-3-yl)pyrido[2,3-dlpyrimidine 3-thiophenecarboxaldehyde 1-hexenyl-boronic acid IR 3300, 3070, 2950, 2850, 1600, 1565, 1330, MS m/z 285 16 4-amino-6-(4-methylphenyl)-7-(5-bromothiophen-2- 5-bromothiophen-2-carboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3450, 3300, 3100, 1640, 1600, 1555, 1425; MS yIOpy ido[2,3-dlpyrimidine acid m/z 397/399 (M+H)Y.

17 14-amino-6-(4-methylphenyl)-7-(5-methylthiophen-2- 15-methylthiophen-2-carboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3460, 3380, 3300, 3150, 1640, 1555, 1445 M LibC/479393spec \jd o0- 1 Ex. Name R 4 Reagent-(7 position) R 3 Reagent-(6-position) Data No.

-yI)pyrido[2,3-dlpyrimidine acid m/z 333 18 4-amino-6-(4-methylphenyl)-7-(4-bromothiophen-2- 4-bromo-thiophen-2-carboxaldehyde 2-(4-methylphenyi)-ethenyl-boronic IR 3320, 3100, 1595, 1555, 1415, 1340, 820; MS m/z yl)pyrido[2,3-dlpyrimidine acid 397, 399 19 4-amino-6-(4-methylphenyl)-7-(3-methylthiophen-2- 3-methyl-thiophen-2-carboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic iR 3300, 3060, 1600, 1550, 1450, 1335, 820; MS m/z yl)pyrido[2,3-d]pyrimidine acid 333 4-amino-6-(4-methylphenyl)-7-(furan-2-y)pyrido[2,3- Furari-2-carboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3430, 3300, 3170, 1630, 1560, 1450, 1340; MS dipyrimidine acid mz33(+) 21 14-amino-6-(4-methylphenyl)-7-(furan-3-y)pyrido[2,3- Furan-3-carboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic IR 3360, 3140, 1655, 1605, 1555, 1340, 1165; MS dipyrimidine acid m/z 303 22 14-amino-6-(4-methylphenyl)-7-(5-methyl-furan-2- 5-methylfuran-2-carboxaldehyde 2-(4-methylphenyl)-ethenyl-boronic I R 3440, 3180, 1630, 1600, 1555, 1335, 820; MS m/z yI)pyrido[2,3-dlpyrimidine acid 317 23 4-amino-6-(4-(2-propyl)phenyl)-7.(thiophen-2-y)pyrido[2,3- Thiophen-2-carboxaldehyde 2-(4-(2-propyl)phenyl)-ethenyl-boronic IR 3460, 3320, 3160, 2960, 1600, 1555, 1425; MS dipyrimidine acid m/z 347 24 4-amino-6-(4-(dimethylamino)phenyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(4-(dimethylamino)phenyl)-ethenyl- IR 3440, 3160, 1610, 1555, 1525, 1340, 820; MS M/z yl)pyrido[2,3-dlpyrimidine boronic acid 348 4-amino-6-(3,4-dimethoxyphenyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(3-4-dimethoxyphenyl)-ethenyl- IR 3420, 3080, 1600, 1560, 1515, 1425, 1340; MS yI)pyrido[2,3-dlpyrimidine boronic acid m/z 365 26 4-amino-6-hexyl-7-(4-(dimethylamino)pheny)pyrido[2,3- 4-(dimethylamino)-benzaldehyde 1-octenyl-boronic acid IR 3320, 3100, 2920, 2850, 1600, 1560, 1335; MS dipyrimidine m/z 350 27 4-am in o-6-hexyl-7-(th ioph en-2-y)pyrido[2,3-dlpyri mid ine Thiophen-2-carboxaldehyde 1-octenyl-boronic acid IR 3320, 3160, 2920, 2840, 1600, 1560, 1425; MS 313 28 4-amino-6-(2-methyl-2-propyl)-7-(thiophen-2-y)pyrido[2,3- Thiophen-2-carboxaldehyde 3,3-dimethyl-1-butenyl-boronic acid IR 3400, 3320, 3180, IR 2960, 1640, 1565, 1335; MS dipyrimidine m/~z 285 29 4-amino-6-(4-(2-propyl)phenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-(2-propyl)phenyl)-etheny-boronic IR 3600, 3250, 2955, 1590, 1555, 1400, 1340, 1195, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine acid 815; MS m/z 384 4-amino-6-(4-propylphenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-propylphenyl)-ethenyi-boronic IR 3520-3250, 2960, 1590, 1555, 1400, 1340, 1195, -(dimetlhylamino)phenyl)pyrido[2,3-dlpyrimidine acid 815; MS mlz 384 31 4-amino-6-(3,4-dimethoxyphenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3,4-dimethoxyphenyl)-ethenyl- IR 3320, 3240-2760, 1590, 1560, 1510, 1515, 1340, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine boronic acid 820; MS m/z 384 32 4-amino-6-(3-methoxyphenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-methoxyphenyl)-ethenyl-boronic IR 3365, 3320, 3250-2780, 1660, 1590, 1560, 1460, -(dimethylamino)phenyl)pyrido[2,3-dlpyrimidine acid 1400, 1200, 820; MS m/z 402 33 4-amino-6-(3-bromophenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-bromophenyl)-ethenyl-boronic IR 3400-3250, 3250-2840, 1660, 1590, 1560, 1340, -(di methylani no) phen yl) pyrido[2,3-dlpyri mid ine acid 1200, 820; MS mlz 420 34 4-amino-6-(3-fluorophenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-fluorophenyl)-ethenyl-boronic acid IR 3520-2800, 1645, 1610, 1590, 1560, 1525, 1400, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine 1 1340, 1200, 820; MS m/z 360 LibC/479393spec ~yd or 9* p S* fX". Name R 4 Reagent-(7 position) R 3 Reagent-(6-position) Data 4-amino-6-(3-trifluoromethylphenyl)-7-(4- 4-(dimethylamino)-benzaidehyde 2-(3-trifluoromethylphenyl)-etheny- IR 3560, 3520, 3240-2840, 1660, 1590, 1560, 1400, -(dimethylamino)phenyl)pyrido[2,3-dlpyimidine acid 1340, 1160,1120, 810, 700; MS m/z410 36 4-amino-6-(3-chlorophenyl)-7-(4- 4-(dimethyiamino)-benzaldehyde 2-(3-chlorophenyl)-ethenyl-boronic IR 3500-3280, 3200-2840, 1660, 1590, 1560, 1395, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine acid 1370, 1340, 1200, 820; MS m/z 376 37 4-amino-6-(3,5-dichlorophenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3,5-dichlorophenyl)-ethenyl-boronic IR 3560-3280, 3240-3300, 1640, 1590, 1560, 1400, (dimethylamino)phenyl)pyridoj2,3-dlpyrimidine acid 1365, 1340, 1195, 820, 800; MS m/z411 38 4-amino-6-(3,4-methylenedioxyphenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3,4-methylenedioxyphenyl)-ethenyl- IR 3600-3280, 3240-3000, 1595, 1560, 1400, 1195, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine boronic acid 1040, 815; MS mlz 386 4-amino-6-(3-methoxycarbonylphenyl)-7-(4- 4-(dimethylamino)-benzaidehyde 2-(3-methoxycarbonylphenyl)-ethenyl- IR 3360, 3320, 3200-3000, 1720, 1660, 1595, 1560, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine acid 1400, 1340,1200, 820; MS n~z 400 41 4-amino-6-(3-(2-propyl)phenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-(2-propyl)phenyl)-ethenyl-boronic IR 3500-3280, 3200-3000, 2960, 1590, 1555, 1395, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine 1340, 1195; MS mlz 384 42 4-amino-6-(4-(2-methyi-2-propyl)phenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-(2-methyl-2-propyl)phenyl)- IR 3520-3280, 3180, 2960, 1590, 1555, 1340, 1195, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine ethenyl-boronic acid 820; MS mlz 398 43 4-amino-6-(4-fluorophenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-fluorophenyl)-ethenyl-boronic acid IR 3490, 3320, 3200-3000, 1590, 1555, 1400, 1340, (dimethylamino)phenyl)pyrido[2,3-d]pyimidine 1195, 820; MS m/z 360 44 4-amino-6-(4-methoxyphenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-methoxyphenyl)-etheny-boronic IR 3370, 3320, 3200-3000, 1660, 1590, 1555, 1400, (dimethylamino)phenyl)pyrido[2,3-djpynmidine acid 1340,1250,1195, 815; MS m/z372 4-amino-6-(3-(phenylmethoxy)phenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-(phenylmethoxy)pheny)-ethenyl- IR 3360, 3320, 3200-3000, 1655, 1590, 1560, 1400, -(dimethylamino)phenyl)pyrido[2,3-dlpyrimidine boronic acid 1195, 820; MS m/z 448 46 4-amino-6-(4-chlorophenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(4-chlorophenyl)-ethenyl-boronic IR 3480-3320, 3200-3020, 1590, 1550, 1410, 1340, (di methylamino) phenyl) pyido[2,3-dlpyri mid ine acid 1195, 815; MS mlz 376 (M+H)Y.

47 4-amino-6-(3-fluoro4methylphenyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-fluoro-4-methylphenyl)-ethenyl- IR 3360, 3160-3000, 1660, 1590, 1555, 1340, 1200, (dimeth ylamino)phen yl)pyrido[2,3-d]pyri mid ine boronic acid 820; MS m/z 374 48 4-amino-6-(3-fluoro-4methyiphenyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(3-fluoro-4-methylphenyl)-ethenyl- IR 3600-3300, 3200, 3020, 1620, 1415; MS m/~z 337 yl)pyrido[2,3-dlpyrimidine boronic acid 49 4-amino-6-(3-phenylpropyl)-7-(4-methoxyphenyl)pyrido[2,3- 4-methoxy-benzaldehyde 5-phenyl-1-pentenyl-boronic acid NMR (00013) 5 8.70 1H), 8.06 1H), 7.53 (d, djpyrimidine J=9Hz, 2H), 7.22 (in, 3H), 7.06 J=8Hz, 2H), 6.94 J=9Hz, 2H), 6.19 br, 2H), 3.88 3H), 2.88 (mn, 2.57 (mn, 2H), 1.88 (mn, 2H); MS m/z 371 4-amino-6-(3-phenylpropyl)-7-(4- 4-(diinethylainino)-benzaldehyde 5-phenyl-1-pentenyl-boronic acid NMR (CDC3) 8 8.73 1H), 7.88 1H), 7.58 (d, dimethylainino)phenyl)pyrido[2,3-djpyrimidine J=8Hz, 2H), 7.22 (in, 3H), 7.10 J=8Hz, 2H), 6.73 J=9Hz, 2H), 5.78 br, 2H), 3.04 6H), 2.96 (in, 2H), 2.61 J=8Hz, 2H), 1.91 (in, 2H); MS m/z 384 LibC/479393spec S S. S S S S S S S 5 S S S. *SS S. 5.5 S. S S. 55 **SS S 55 S S S 55555 5 S S S S *5 55 5. 55*5 d~ (~3 E. tame R 4 Reagent-(7 position) R 3 Reagent-(6-position) Data Ao.

51 4-amino-6-(2-phenylethyl)-7-(4- 4-(dimethylamino)-benzaldehyde 4-phenyl-1-butenyl-boronic acid NMR (C~DC 3 8 8.75 1 7.69 1 7.65 (in, (dimethylamino)phenyl)pyrido[2,3-dlpyrimidine 2H), 7.21 (in, 3H), 7.04 (mn, 2H), 6.79 (in, 2H), 5.57 br, 2H), 3.25 (mn, 2H), 3.04 6H), 2.85 (in, 2H); m/z 370 52 4-amino-6-(phenylmethyl)-7-(4- 4-(diinethylamino)-benzaldehyde 3-phenyl- 1-propenyl-boronic acid NMR (00013) 8 8.74 1 7.74 1 7.65 (d, (diineth ylamino)phenyl)pyrido[2,3-d]pyri mid ine J=9Hz, 2H), 7.30 (mn, 3H), 7.10 (in, 2H), 6.74 (d, J=9Hz, 2H) 5.64 br, 2H), 4.29 2H), 3.02 (s, 6H); MS m/z 356 53 4-amino-6-butyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- 4-(dimethylamino)-benzaldehyde 1-hexenyl-boronic acid NMR (CDC3) 5 8.74 1 7.96 1 7.62 (d, dipyrimidine J=9Hz, 2H), 6.77 J=9Hz, 2H), 5.86 2H), 3.04 6H) 2.91 (in, 2H), 1.57 (in, 2H), 1.32 (sextet, 2H), 0.87 J=7Hz, 3H); MS m/z 322 54 4-ainino-6-pentyl-7-(4-(diinethylainino)phenyl)pyrido[2,3- 4-(dimethyiamino)-benzaidehyde 1 -heptenyl-boronic acid NMR (DMSO-d6) 858.53 1 8.45 1 7.47 (d, djpyrimidine J=8Hz, 2H), 6.82 J=8Hz, 2H), 3.34 1H), 3.32 1H) 2.99 6H), 2.81 (in, 2H), 1.58 (in, 2H), 1.23 (in, 4H), 0.82 (in, 3H); MS m/z 336 4-ainino-6-(2-methylpropyl)-7-(4- 4-(dimethylainino)-benzaldehyde 4-inethyl-1-pentenyl-boronic acid NMR (00013) 5 8.76 1H), 7.88 1H), 7.61 (d, (diinethylainino)phenyl)pyrido[2,3-dlpyrimidine J=9Hz, 2H), 6.77 J=9Hz, 2H), 5.76 br, 2H), 3.03 6H) 2.84 J=7Hz, 2H), 1.78 (in, 1H), 0.78 J=6Hz, 6H); MS mlz 322 56 4-ainino-6-propyl-7-(4-(dimethylamino)phenyl)pyrido[2,3- 4-(diinethylamino)-benzaldehyde 1 -pentenyl-boronic acid NMR (DMSO-d6) 8 8.52 1 8.45 I1H), 7.90 (s, dipyriinidine br, 2H), 7.48 J=8Hz, 2H), 6.82 J=8Hz, 2H), 2.99 6H), 2.80 (in, 2H) 1.60 (sextet. J=7Hz, 2H), J=7Hz, 3H); MS m/z 308 57 4-amino-6-(3-cyanopropyl)-7-(4- 4-(diinethylainino)-benzaldehyde 5-cyano-1-pentenyl-boronic acid NMR (DMSO-d6) 58.56 1 8.47 1 7.94 (s, (diinethylamino)phenyl)pyrido[2,3-dlpyriinidine br, 2H), 7.50 J=9Hz, 2H), 6.83 J=9Hz, 2H), 3.00 6H), 2.93 (in, 2H) 2.50 (in, 2H), 2.50 (in, 2H), 1.90 MS m/~z 333 58 4-ainino-6-pentyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine Thiophen-2-carboxaldehyde 1 -heptenyl-boronic acid JR 3320, 3100, 1560, 1430; MS ml~z 299 59 4-amino-6-(3-carboxainidopropyl)-7-(4- 4-(diinethylamino)-benzaldehyde 5-cyano-1-pentenyl-boronic acid IR 3325, 3120, 1660, 1595; MS m/z 351 (dimethylamino)phenyl)pyrido[2,3-dlpyriinidine 4-amino-6-((4-methoxyphenyl)methyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2.(4-methoxyphenyl)-propenyl boronic IR 3360, 3100, 1605, 1565; MS m/vz 349 yl)pyrido[2,3-dlpyrimidine acid 61 4-ainino-6-((3-bromophenyl)methyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(3-bromophenyl)-propenyl boronic IR 3440, 3120, 1605, 1565; MS m/z 397/399 yl)pyrido[2,3-dlpyriinidine acid LibC/479393spec ~yd #s1) 0 0 0.0 00 *toa a EW'Name R 4 Reagent-(7 position) R 3 Reagent-(6-position) Data No. 62 4-amino-6-((4-(2-propyl)phenyl)methyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(4-(2-propyl)phenyl)-propenyl IR 3440, 3080, 1600, 1560; MS m/z 361 yI)pyrido[2,3-d]pyrimidine boronic acid 63 4-amino-6-((4-methoxyphenyl)methyl)-7-(4-(2- 4-isopropyl-benzaldehyde 2-(4-methoxyphenyl)-propenyl boronic IR 3360, 3120, 1565, 1510; MSm/z 385 propyl)phenyl)pyrido[2,3-dlpyrimidine acid 64 4-amino-6-((4-bromophenyl)methyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(4-bromophenyl)-propenyl boronic IR 3440, 3160,1625,1560; MS mlz 397/399 yI)pyrido[2,3-d~pyrimidine acid 4-amino-6-((3-fluorophenyl)methyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(3-fiuorophenyl)-propenyl boronic I R 3320, 3160, 1600, 1560; MS m/z 337 yl)pyrido[2,3-dlpyrimidine acid 66 4-amino-6-((4-bromophenyl)methyl)-7-(thiazole-2- Thiazole-2-carboxaldehyde 2-(4-bromophenyl)-propenyl boronic IR 3450, 3100, 1635, 1560; MS m/z 398/400 yl)pyrido[2,3-d]pyrimidine acid 67 4-amino-6-((3-methoxyphenyl)methyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 2-(3-methoxyphenyl)-propenyl boronic IR 3450, 3150, 1600, 1560; MS m/z 349 yI)pyrido[2,3-dlpyrimidine acid 68 4-amino-6-(phenymethyl)-7-(thiophen-2-y)pyrido[2,3- Thiophen-2-carboxaldehyde 2-phenyl-1-propeny boronic acid IR 3390, 3110, 1605, 1565; MS mlz 319 dipyrimidine 69 4-amino-6-((3-methoxyphenyl)methyl)-7-(4- 4-(dimethylamino)-benzaldehyde 2-(3-methoxyphenyl)-propenyl boronic IR 3310, 3080, 1600, 1565; MS m/z 386 (dimethylamino)phenyl)pyrido[2,3-djpyrimidine acid 4-amino-6-(4-methylphenyl)-7-(4- 4-(trifluoromethyl)-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3230,1325, 820; MS m~lz 381 (trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidine 71 4-amino-6-(4-methylphenyl)-7-(4-(methylphenyl)pyrido[2,3- 4-methyl-benzaldehyde 2-(4-methylphenyl)-etheny boronic IR 3450, 1449,1340, 820; MS mlz 327 -dipyrimidine 72 4-amino-6-(4-methylphenyl)-7-(4-(methoxyphenyl)pyrido[2,3- 4-methoxy-benzaidehyde 2-(4-methylphenyl)-ethenyl boronic IR 3375, 1600, 820; MS m/z 343 dipyrimidine acid 73 4-amino-6-(4-methylphenyl)-7-(4-ethylphenyl)pyido[2,3- 4-ethyl-benzaldehyde 2-(4-methytphenyl)-ethenyl boronic IR 3340,1558,1340, 820; MS m/z 341 dipyrimidine acid 74 4-amino-6-(4-methylphenyi)-7-(4-cyanophenyl)pyrido[2,3- 4-cyano-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3320,1560, 820; MS mlz338 dipyrimidine acid 4-amino-6-(4-methylphenyl)-7-(4- 4-acetamido-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3325,1520, 820; MS m/z 370 acetamidophenyl) pyrido [2,3-d]pyri mid ine acid 76 4-amino-6-(4-methylphenyl)-7-(4-fiuorophenyl)pyido[2,3- 4-fluoro-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3320, 1550, 1340, 840; MS m/z 331 (M+H) dipyrimidine acid 77 4-amino-6-(4-methylphenyI)-7-(4-chiorophenyI)pyrido[2,3- 4-chloro-benzaldehyde 2-(4-methylphenyl)-etheny boronic IR 3340,1550,1340, 910; MS m/z 347 dipyrimidine acid 78 4-amino-6-(4-methylphenyl)-7-(4-aminophenyl)pyrido[2,3- 4-amino-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3325, 1550, 820; MS mlz 328 -dipyrimidine acid 79 4-amino-6-(4-methylphenyl)-7-((4- 14-phenylmethoxy-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3400,1340,1245, 700; MS m/z 419 (M+H)Y.

LibC/479393spec dV 0 S. *5 9. 5 S U S 99 9 9 9 U 9 9 9 S. 9. 26 .5 9 *9 99 **99 9 9 59 9 ,~9 9 9 99999 5 *9 S 9 *5

-C'

to 1Name

R

4 Reagent-(7 position) R 3 Reagent-(6.position) Data -phenylmethoxy)phenyl)pyrido[2,3-dlpyrimidine acid 4-amino-6-(4-methyphenyl)-7-((4-NN- 4-(NN-diethylamino)-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3330, 1550, 1200, 819; MS mlz 384 diethylamino)phenyl)pyrido[2,3-dlpyrimidine 81 4-amino-6-(4-methylphenyl)-7-((4-2- 4-(2-phenylethenyl)-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3460, 1600, 1340, 690; MS M/z 415 phenylethenyl)phenyl)pyrido[2,3-dlpyrimidine 82 4-amino-6-(4-methylphenyl)-7-(4-2-methyl-2- 4-(2-methyl-2-propoxy)-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3315, 1550, 1160, 900; MS m/z 385 propoxy)phenyl)pyrido[2,3-d]pyrimidine acid 83 4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl)pyrido[2,3- 3-chloro-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3050,1555, 1340, 825; MS m/z 347 dipyrimidine 84 4-amino-6-(4-methylphenyl)-7-(3,5- 3,5-dimethoxy-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3430, 1600, 1200, 720; MS m/z 373 dimethoxyphenyl)pyrido[2,3-d]pyrimidine acid 4-amino-6-(thiophen-2-y)-7-(4-NN- 4-(NN-dimethylamino)-benzaldehyde 2-(thiophen-2-yI)-ethenyl boronic acid IR 3320, 1590, 700; MS mlz348 86 4-amino-6-(4-methylpheny)-7-(benzofuran-2-y)pyido[2,3- Benzofuran-2-Garboxaldehyde 2-(4-methylphenyl)-ethenyl boronic IR 3310, 1640, 750; MS m/z 353 dipyrimidine acid 87 4-amino-6-(thiophen-2-y)-7-(thiophen-2-y)pyrido[2,3- Thiophen-2-carboxaldehyde 2-(thiophen-2-yI)-ethenyl boronic acid IR 3315, 1560, 1420, 700; MS M/z 311 dipyrimidine 88 4-amino-6-(thiophen-2-yl)-7-(4-methoxyphenyl)pyrido[2,3- 4-methoxy-benzaidehyde 2-(thiophen-2-yI)-ethenyl boronic acid IR 3400, 1560,1250, 835; MSm/z 335 1dipyrimidine 89 4-amino-6-(4-bromophenyl)-7-(4-NN- 4-(NN-dimethylamino)-benzaldehyde 2-(4-bromophenyl)-ethenyl boronic IR 3330, 1545, 1190, 810; MS mlz420 dimethylphenyl)pyrido[2,3-dlpyrimidine acid 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(4-NN- 4-(NN-dimethylamino)-benzaldehyde 2-(3-bromo-4-methoxy-phenyl)-etheny IR 3380, 1590, 1200, 820; MS m/z 415 dimethylphenyl)-pyrido[2,3-dlpyrimidine boronic acid 91 4-amino-6-(3-bromo-4-methoxy-phenyl)-7-(thiophen-2- Thiophen-2-carboxaldehyde 3- 2-(3-bromo-4-methoxy-phenyl)-etheny IR 3400, 1550, 1280, 715; MS m/lz 414 yl)pyrido[2,3-dlpyrimidine acid 92 4-amino-6-(4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3- 4-butoxybenzaldehyde 2-(4-methylphenyl)-ethenyl boronic Na dipyrimidine acid 93 4-amino-6-(4-methytphenyl)-7-(3-methoxyphenyl)pyrido[2,3- 3-methoxybenzaldehyde 2-(4-methylphenyl)-ethenyl boronic Na dipyr midine acid 94 4-amino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3- 3,5-dichloro-benzaldehyde 2-(4-methylphenyl)-ethenyl boronic Na dlpyrimidine acid LibC/479393spec

Claims

1. A compound of formula 1: 12 R~ 4 or a pharmaceutically acceptable salt thereof, wherein R, and R 2 are independently selected from the group consisting of hydrogen and loweralkyl; R 3 is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl and heterocycle; and R 4 is selected from the group consisting of aryl and heterocycle; wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of F, Cl, Br, 1, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamnino, di(loweralkyl)amino, N-loweralkyl-N-loweralkoxyamino, trifluoromethyl, and methoxymethyl. A compound according to claim 1 wherein R, and R2 are hydrogen; R3 is selected from the group consisting of alkyl, aryl, and arylalkyl; and R 4 is aryl; wherein, for the foregoing R3, the aryl and aryl part of the arylalkyl are unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, dialkylamino, F, Cl, Br, trifluoromethyl, and methylenedioxy; and wherein, for the foregoing R 4 the aryl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, cyano, amino, dialkylamino, halo, trifluoromethyl, and methylenedioxy. A compound according to claim 1 or claim 2 wherein R 3 is selected from the group 20 consisting of 3-bromo-4-methoxyphenyl, 3-bromophenyl, 4-bromophenyl, 4-butoxyphenyl, butyl, 3- chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3,4-dimethoxyphenyl, 4-(1 ,1 -dimethylethyl)phenyl,

4-(dimethylamino)phenyl, 3-fluoro-4-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, hexyl, 3-methoxy phenyl, 4-methoxyphenyl, (3-methoxyphenyl)methyl, (4-methoxyphenyl)methyl, 3,4-methylenedioxy phenyl, 4-methylphenyl, 2-methylpropyl, pentyl, 2-phenylethyl, phenylmethyl, 3-phenylpropyl, propyl, 4-propylphenyl, 3-(2-propyl)phenyl, 4-(2-propyl)phenyl, and 3-trifluoromethylphenyl. 4. A compound according to any one of claims 1 to 3 wherein R 4 is selected from the group consisting of (4-aminophenyl), (4-bromophenyl), (3-chlorophenyl), (4-chlorophenyl), (4-cyanophenyl), (4-(diethylamino)phenyl), (3,5-dimethoxyphenyl), (4-(dimethylamino)phenyl), (4- ethylphenyl), (4-fluorophenyl), (3-methoxyphenyl), (4-methoxyphenyl), (4-methylphenyl), (3,4- methylenedioxyphenyl), phenyl, 4-(2-propyl)phenyl, (4-(tert-butoxy)phenyl), and 4-(trifluoromethyl) phenyl. A compound selected from 4-amino-6-phenyl-7-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-dlpyrimidime; 4-amino-6-(4-(dimethylami no)phenyl)-7-(4-(d imethylam ino)phenyl) pyrido[2,3-d]pyri mid ine; 4-amino-6-(4-methylphenyl)-7-phenylpyrido[2,3-dpyrimidine; j~Tl4'4;amino6(4methylphenyl)7(4bromophenyl)pyrido[2,3d]pyrimidine; (_j LibC/479393spec 28 4-amino-6-(4-(dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3,4-methylenedioxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-hexyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-amino-6-(4-propylphenyI)-7-(4-(dimethylamino)pheny)pyddo2,3-d~pyrimidime; 4-amino-6-(3,4-d imethoxyphenyl)-7-(4-(d imethyl amino)phenyl) pyrido[2,3-d]pyri mid ine; 4-amino-6-(3-methoxyphenyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-bromophenyl)-7-(4-(d imethyl amino) phenyl)pyrido[2,3-d]pyri mid ine; 4-amino-6-(3-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-trifluoromethylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3,5-dichlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-djpyrimidine; 4-amino-6-(3,4-methylened ioxyphenyl)-7-(4-(d imethyl amino) phenyl) pyrido[2,3-d]pyri mid ine; 4-amino-6-(3-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-(1,1 -dimethylethyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-fl uorophenyl)-7-(4-(d imethylamino) phen yl)pyrido[2,3-d]pyri mid ine; 4-amino-6-(4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-dpyrimidine; 4-amino-6-(4-chlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-fl uoro-4-methylphenyl)-7-(4-(dimethylam ino) phenyl)pyrido[2,3-d] pyri mid ine; 4-amino-6-(3-phenyl propyl)-7-(4-methoxyphenyl) pyrido[2,3-d]pyri mid ine; 4-amino-6-(3-phenylpropyl)-7-(4-(dimethylamino)pheny)pyrido[2,3-d]pyrimidime; 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-butyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-am ino-6-pentyl-7-(4-(d imethylamino) phenyl) pyndo[2,3-djpyri mid ine; 4-amino-6-(2-methylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-dlpyrimidine; 4-am ino-6-propyl-7-(4-(d imethylamino)phenyl)pyrido[2,3-dpyri mid ine; 4-amino-6-((4-methoxyphenyl)methyl)-7-(4-(2-propyl)phenyl)pyrido[2,3-dlpyrimidine; 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-am ino-6-(4-methylphenyl)-7-(4-methoxyphenyl) pyrido[2,3-d]pyri mid ine; 4-amino-6-(4-methylpheny)-7-(4-ethylpheny)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-cyanophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(4-chlorophenyl)pyido[2,3-d]pynmidine; 4-amino-6-(4-methylphenyl)-7-(4-aminophenyl)pyrido[2,3-d]pyrimidine; T 4-amino-6-(4-methylphenyl)-7-(4-d iethyl amino) phen yl) pyido[2,3-d]pyri mid ine; 4 4-amino-6-(4-methylphenyl)-7-(4-tet-butoxy)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl)pyrido[23-d]pyrimidine; LibC/479393spec 29 4-amino-6-(4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-bromophenyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(4-dimethylamino)phenyl)pyrido[2,3-d]pyrimidine; 4-amino-6-(3-bromo-4-methoxyphenyl)-7-(thien-2-yl)pyrido[2,3-d]pyrimidine; 4-amino-6-(4-methylphenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; and 4-amino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-d]pyrimidine.

6. A 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine derivative, substantially as hereinbefore described with reference to any one of the examples.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 in combination with a pharmaceutically acceptable carrier.

8. A method of inhibiting adenosine kinase comprising exposing an adenosine kinase to an effective inhibiting amount of a compound according to any one of claims 1 to 6.

9. A method of treating ischaemia, neurological disorders, nociperception, inflammation, 15 immunosuppression, gastrointestinal dysfunctions, diabetes and sepsis in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 6 or of a composition according to claim 7.

10. A compound according to any one of claims 1 to 6 or a composition according to claim :12 when used in treating ischaemia, neurological disorders, nociperception, inflammation, 20 immunosuppression, gastrointestinal dysfunctions, diabetes and sepsis.

11. A compound according to any one of claims 1 to 6 or a composition according to claim 7 for use in treating ischaemia, neurological disorders, nociperception, inflammation, Simmunosuppression, gastrointestinal dysfunctions, diabetes and sepsis.

12. The use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for treating ischaemia, neurological disorders, nociperception, inflammation, immunosuppression, gastrointestinal dysfunctions, diabetes and sepsis.

13. A method, compound, composition or use according to any one of claims 9 to 12, wherein the method consists of treating cerebral ischaemia, myocardial ischaemia, angina, coronary artery bypass graft surgery, percutaneous transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy, anxiety, schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis, sepsis, diabetes and abnormal gastrointestinal motility.

14. A process for the preparation of a compound having the formula R 1 N R 2 RN H wherein R 1 and R 2 are hydrogen, R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, or a heterocyclic group; R 4 is aryl, or a heterocyclic group wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three Ssubstituents independently selected from the group consisting of F, Cl, Br, I, cyano, carboxamido, LibC/479393spec hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkyl)amino, N-loweralkyl-N-loweralkoxyamino, trifluoromethyl, and methoxymethyl; the method comprising reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid derivative having the formula HO I HO' R3, wherein R 3 is as defined above in the presence of tetrakistriphenylphosphinepalladium(0) and an aqueous alkali metal base, and isolating a first NH 2 intermediate compound having the formula H 2 reacting the first intermediate compound with an aldehyde compound having the formula R 4 -CHO, wherein R 4 is as defined above under anhydrous conditions and with the removal of the water of 10 reaction, and isolating the compound of formula I.

15. A process for the preparation of a compound having the formula R1 R2 NR H R 3 (I) wherein R 1 and R 2 are independently H, loweralkyl, with the requirement that not both R 1 and R 2 may be hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, or a heterocyclic group; R 4 is aryl or a heterocyclic group wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of F, Cl, Br, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkyl)amino, N-loweralkyl-N- loweralkoxyamino, trifluoromethyl, and methoxymethyl; the method comprising R R 2 N H N I R 3 reacting a compound having the formula N R wherein R 1 and R 2 are hydrogen; R 3 and R 4 are as defined above with a compound selected from the group consisting of an alkylating agent R 1 wherein R 1 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an arylalkylating agent Rl-loweralkyl-Y, wherein R 1 is arylalkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R 1 -Z, wherein R 1 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the desired compound; and optionally, when it is desired that R 2 should not be hydrogen, treating the compound from step (a) with a compound selected from the group consisting of an alkylating agent R2-Y, wherein R 2 is loweralkyl and Y is selected from the group consisting of a halide, a mesylate and a tosylate; (ii) an <prylalkylating agent R 2 -loweralkyl-Y, wherein R 2 is arylalkyl and Y is selected from the group OFFV// LibC/479393spec 31 consisting of a halide, a mesylate and a tosylate; (iii) an acyl compound R 2 wherein R 2 is an acyl group and Z is selected from the group consisting of an acid anhydride moiety, a halide or an acyl activating group; and isolating the compound of formula I.

16. A process for the preparation of a compound having the formula R 1 R 2 'N H wherein R 1 and R 2 are independently H or loweralkyl with the proviso that not both R 1 and R 2 are hydrogen; R 3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl or a heterocyclic group; R 4 is aryl, or a heterocyclic group wherein each of the foregoing aryl and heterocycle, and the aryl part of the arylalkyl, is unsubstituted or substituted with one, two, or three substituents independently selected 10 from the group consisting of F, Cl, Br, I, cyano, carboxamido, hydroxy, loweralkoxy, loweralkyl, loweralkenyl, loweralkynyl, amino, loweralkylamino, di(loweralkyl)amino, N-loweralkyl-N- loweralkoxyamino, trifluoromethyl, and methoxymethyl; the method comprising reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid derivative having the SHO I formula HOB" R R wherein R 3 is as defined above in the presence of 15 tetrakistriphenylpposphinepalladium(0) and an aqueous alkali metal base, and isolating a first CI 3 0R intermediate compound having the formula NH 2 reacting the first intermediate compound with an aldehyde compound having the formula R 4 -CHO, wherein R 4 is as defined above under anhydrous conditions and with the removal of the water of Cl H R 3 OO 4 reaction, and isolating the second intermediate compound having the formula treating the fourth intermediate compound with an amine compound having the formula R 1 -NH-R 2 wherein R 1 and R 2 are as described above, and isolating the compound of formula I.

17. A compound of the formula: X H R 3 LO 0 R4 N R 4 wherein X is selected from halogen or OH and R 3 and R 4 are as defined in claim 1. Dated 17 October 2001 ABBOTT LABORATORIES Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON LibC/479393spec U ril