ZA200403485B - A2B adenosine receptor antagonists. - Google Patents

Description

Asp ADENOSINE RECEPTOR ANTAGONISTS

Priority is claimed to U.S. Provisional Patent Application Serial No. 60/348,222, filed

November 9, 2001, and U.S. Provisional Patent Application Serial No. 60/401,408, filed August . 3, 2002, the complete disclosures of which are hereby incorporated by reference. . Field of the Invention

The present invention relates to A,p adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as gastrointestinal disorders, immunological disorders, neurological disorders, and cardiovascular diseases due to both cellular hyperproliferation and apoptosis, and the like. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

Background

Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A, Aza, Asp, and As, all of which modulate important physiological processes. For example, Aza adenosine receptors modulate coronary vasodilation, A,p receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A,p Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al.,

Trends Pharmacol Sci 19:148-153), and A; adenosine receptors modulate cell proliferation processes.

Adenosine Ap receptors are ubiquitous, and regulate multiple biological activities. For example, adenosine binds to Ap receptors on endothelial cells, thereby stimulating angiogenesis.

Adenosine also regulates the growth of smooth muscle cell populations in blood vessels. : 25 Adenosine stimulates Ap receptors on mast cells, thus modulating Type I hypersensitivity reactions. Adenosine also stimulates gastrosecretory activity by ligation with Ajp in the intestine.

While many of these biological effects of adenosine are necessary to maintain normal tissue homeostasis, under certain physiological changes it is desirable to modulate its effects.

For example, the binding of Asp receptors stimulates angiogenesis by promoting the growth of * endothelial cells. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels ) occurs in neoplasia. Accordingly, inhibition of the binding of adenosine to Ap receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibibiting tumor formation.

Ap receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and when acted upon by the appropriate ligand act to increase chloride secretion, thus causing diarrhea, which is a common and potentially fatal complication of infectious diseases . such as cholera and typhus. Ap antagonists can therefore be used to block intestinal chloride secretion, and are thus useful in the treatment of inflammatory gastrointestinal tract disorders, : including diarrhea.

Insensitivity to insulin exacerbates diabetes and obesity. Insulin sensivity is decreased by the interaction of adenosine with Ap receptors. Thus, blocking the adenosine A,p receptors of individuals with diabetes or obesity would benefit patients with these disorders.

Another adverse biological effect of adenosine acting at the Ap receptor is the over- stimulation of cerebral IL-6, a cytokine associated with dementias and Altheimer’s disease.

Inhibiting the binding of adenosine to Ap receptors would therefore mitigate those neurological + disorders that are produced by IL-6.

Type I hypersensitivtiy disorders, such as asthma, hay fever, and atopic ezcema, are stimulated by binding to Ajp-receptors of mast cells. Therefore, blocking these adenosine receptors would provide a therapeutic benefit against such disorders. :

There are several compounds presently used in the treatment of asthma. For example, theophylline is an effective antiasthmatic agent, even though it is a poor adenosine receptor antagonist. However, considerable plasma levels are needed for it to be effective. Additionally, theophylline has substantial side effects, most of which are due to its CNS action, which provide no beneficial effects in asthma, and to the fact that it non-specifically blocks all adenosine receptor subtypes.

Additionally adenosine treatment, such as inhaled adenosine (or adenosine monophosphate), provokes bronchoconstriction in asthmatics, but not in the normal population.

This process is known to involve mast-cell activation, in that it releases mast cell mediators, including histamine, PGD2- B-hexosaminidase and tryptase, and because it can be blocked by specific histamine H; blockers and chromolyn sodium. Accordingly, there is an intrinsic difference in the way adenosine interacts with mast cells from asthmatics, and thus Asp antagonists are particularly useful in modulating mast cell function or in the activation of human lung cells. ’ Accordingly, it is desired to provide compounds that are potent Ap antagonists, fully or ; partially selective for the Asp receptor, useful in the treatment of various disease states related to modulation of the A,p receptor, for example cancer, asthma and diarrhea.

SUMMARY OF THE INVENTION

It is an object of this invention to provide A,p receptor antagonists. Accordingly, in a first aspect, the invention relates to compounds of Formula I and Formula II: . . } . 0 Rh J RN n

N N

PY | xv PY | Hera o N N o N N

L l, Ne

Formula I Formula II wherein:

R! and R? are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-

E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy;

R3is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

X is optionally substituted arylene or optionally substituted heteroarylene;

Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by -O-, -S- , or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or -COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and

Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or 'Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond; with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.

A second aspect of this invention relates to pharmaceutical formulations, comprising a . 25 therapeutically effective amount of a compound of Formula I or Formula II, or a mixture thereof, and at least one pharmaceutically acceptable excipient. . A third aspect of this invention relates to a method of using the compounds of Formula I and Formula II in the treatment of a disease or condition in a mammal that can be usefully treated with an Ap receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I or Formula II, or a mixture thereof.

Such diseases include, but are not limited to, at least one of asthma, inflammatory : gastrointestinal tract disorders, including diarrhea, cardiovascular diseases such as atherosclerosis, neurological disorders such as senile dementia, Alzheimer’s disease, and : Parkinson’s disease, and diseases related to angiogenesis, for example diabetic retinopathy and cancer. ! A fourth aspect of this invention relates to methods for preparing the compounds of

Formula I and Formula II.

One preferred group of compounds of Formula I and II are those in which R! and R* are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, particularly those in which R? is hydrogen.

Within this group, a first preferred class of compounds include those in which R' and R® are independently lower alkyl optionally substituted by cycloalkyl, preferably n-propyl, and X is optionally substituted phenylene. Within this class, a preferred subclass of compounds are those in which Y is alkylene, including alkylene in which a carbon atom is replaced by oxygen, preferably -O-CH,-, more especially where the oxygen is the point of attachment to phenylene.

Within this subclass, it is preferred that Z is optionally substituted oxadiazole, particularly optionally substituted [1,2,4]-oxadiazol-3-yl, especially [1,2,4]-oxadiazol-3-yl substituted by optionally substituted phenyl.

A second preferred class of compounds include those in which X is optionally substituted 1,4-pyrazolene. Within this class, a preferred subclass of compounds are those in which Y is alkylene, especially lower alkylene, and Z is hydrogen, optionally substituted phenyl or optionally substituted oxadiazole. Within this subclass, one preferred embodiment includes compounds in which R! is lower alkyl optionally substituted by cycloalkyl, and R%is hydrogen.

A more preferred embodiment includes those compounds in which Y is -(CH,)- or -CH(CH3)- and Z is optionally substituted phenyl. Another preferred embodiment includes those compounds in which Y is -(CHa)- or -CH(CH3)- and Z is optionally substituted oxadiazole, + particularly 3,5-[1,2,4]-oxadiazole. Within this subclass, also preferred are those compounds in which R! and R? are independently lower alkyl optionally substituted by cycloalkyl, especially n- propyl. More preferred are those compounds in which Y is a covalent bond, -(CHy)- or -CH(CHs)- and Z is hydrogen or optionally substituted phenyl, particularly where Y is a covalent bond and Z is hydrogen.

At present, the preferred compounds are: 1-propyl-8-(1-{[3-(triflucromethyl)phenyl]-methyl} pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione; 1-butyl-8-(1-{[3-fluorophenyljmethyl} pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione; 1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione; : 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)| methyl} pyrazol-4-yl)-1-propyl-1,3,7- trihydropurine-2,6-dione; 4 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl) methyl} pyrazol-4-yl)-1-butyl-1,3,7- trihydropurine-2,6-dione; 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione; 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione; l-cyclopropylmethyl-3-methyl-8-{1-[(3 -trifluoromethylphenyl)methyl]pyrazol-4-yl} -1,3,7- trihydropurine-2,6-dione; 1,3-dimethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione; 3-methyl-1-propyl-8- {1-[(3-triflucromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine- 2,6-dione; 3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6- dione; 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl methyl } pyrazol-4-yl)-1,3,7-trihydropurine-2,6- dione; 1,3-dipropyl-8-{1-[(3-fluorophenyl)methyljpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione; 1-ethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione; 1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-y1}-1,3,7-trihydropurine-2,6-dione; 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)-phenyl]ethyl} pyrazol-4-yl)-1,3,7-trihydropurine-2,6- dione; 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione; 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl}-2-phenylacetic acid; 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7- trihydropurine-2,6-dione; 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7- trihydropurine-2,6-dione; and 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7- ] trihydropurine-2,6-dione.

Definitions and General Parameters

As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

The term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3,4,5,6,7,8,9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19 or 20 carbon atoms. . This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, X t-butyl, n-hexyl, n-decyl, tetradecyl, and the like. 8 The term “substituted alkyl” refers to: 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO;-aryl and -SO,- heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O)uR, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2; or 2) an alkyl group as defined above that is interrupted by 1-10 atoms independently chosen from oxygen, sulfur and NR,-, where R, is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CFs, amino, substituted amino, cyano, or —S(O).R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2; or 3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-10 atoms as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6¢carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted " alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1,2, 3, 4, 5,6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms,

This term is exemplified by groups such as methylene (-CH;-), ethylene (-CH,CH,-), the propylene isomers (e.g., -CH,CH,CH,- and-CH(CH3)CH,-) and the like.

The term “lower alkylene” refers to a diradical of a branched or unbranched saturated . hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.

The term “lower alkylene” refers to a diradical of a branched or unbranched saturated ¥ hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.

The term“substituted alkylene” refers to: (1) an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, ~-SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO,- heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O),R, where R is alkyl, aryl, or heteroaryl and nis 0,1o0r2;0r (2) an alkylene group as defined above that is interrupted by 1-20atoms independently chosen from oxygen, sulfur and NR,-, where R, is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or (3) an alkylene group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of substituted alkylenes are chloromethylene (-CH(CI)-), aminoethylene (-CH(NH;)CH,-), methylaminoethylene (-CH(NHMe)CHj-), 2-carboxypropylene isomers(-

CH,CH(CO,H)CHj;-), ethoxyethyl (-CH,CH,0-CH,CH,-), ethylmethylaminoethyl (-

CH,CH,N(CH3)CH,CH,-),1-ethoxy-2-(2-ethoxy-ethoxy)ethane (-CH,CH,0-CH,CH,-

OCH;CH,-OCH,CH>-), and the like.

The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where ) aryl and alkylene are defined herein. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like. . The term “alkoxy” refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy groups are optionally substituted alkyl-O- and include, by way . of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-- pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

N The term “alkylthio” refers to the group R-S-, where R is as defined for alkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl). Preferred alkenyl groups include ethenyl or vinyl (-CH=CH,), 1-propylene or allyl (-

CH,CH=CHy), isopropylene (-C(CH3)=CHy,), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl! as defined above having from 2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of - alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, : aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO»-alkyl, SO»-aryl and -SO;-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFs, amino, substituted amino, cyano, and —S(O),R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (-C=CH), propargyl (or prop-1-yn-3-yl, -CH,C=CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,

aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, : hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO;-heteroaryl. Unless otherwise constrained by the definition, all substituents may ’ optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O),R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “aminocarbonyl” refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O)R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “acylamino” refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and ~S(O),R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “acyloxy” refers to the groups —O(0)C-alkyl, -O(0)C-cycloalkyl, -0(0)C- aryl, —O(O)C-heteroaryl, and —O(0O)C-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —-S(O)R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a - single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.

The term “arylene” refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, 1,4’-biphenylene, and the like. ]

Unless otherwise constrained by the definition for the aryl or arylene substituent, such aryl or arylene groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, ,

heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -

SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO-aryl and -SO,-heteroaryl. Unless otherwise constrained : by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, ' substituted amino, cyano, and —S(O),R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term “arylthio™ refers to the group R-S-, where R is as defined for aryl. }

The term “amino” refers to the group -NHa,.

The term “substituted amino” refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl, Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3;, amino, substituted amino, cyano, and —S(O)sR, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “carboxyalkyl” refers to the groups -C(O)O-alkyl, -C(0)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(0),R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “cycloalkyl” refers to carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, 1,3,3- trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having 1,2, 3,4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, } aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO;-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be furiher substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, : and —S(O),R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo. ’ The term “acyl” denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

The term “heteroaryl” refers to an aromatic cyclic group (i.e., fully unsaturated) having 1, 2,3,4,5,6,7,8,9,10,11, 12, 13, 14, or 15 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl). Examples of heteroaryls include, but are not limited to, [1,2,4]oxadiazole, [1,3,4]oxadiazole, [1,2,4]thiadiazole, [1,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, ‘pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N- alkoxy-nitrogen containing heteroaryl compounds.

The term “heteroarylene” refers to a diradical of a heteroaryl group as defined above.

This term is exemplified by groups such as 2,5-imidazolene, 3,5-[1,2,4]oxadiazolene, 2,4- oxazolene, 1,4-pyrazolene, and the like. For example, 1,4-pyrazolene is:

J»

N——A

ESS

A where A represents the point of attachment. :

Unless otherwise constrained by the definition for the heteroaryl or heteroarylene substituent, such heteroaryl or heterarylene groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, ‘ alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, : 30 carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO»-alkyl, SO,-aryl and -SO,-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF, amino, substituted amino, cyano, and -S(O).R, . where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “heteroaralkyl” refers to a heteroaryl group covalently linked to an alkylene : group, where heteroaryl and alkylene are defined herein. “Optionally substituted heteroaralkyl” refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group. Such heteroaralkyl groups are exemplified by 3-pyridylmethyl, quinolin-8- ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.

The term “heteroaryloxy” refers to the group heteroaryl-O-.

The term “heterocyclyl” refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholino, piperidinyl, piperazino, dihydropyridino, and the like.

Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -

SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO;-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFs, amino, substituted amino, cyano, and —S(O),R, where R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “thiol” refers to the group -SH. - The term “substituted alkylthio” refers to the group —S-substituted alkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.

The term “sulfoxide” refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl. “Substituted sulfoxide” refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

The term “sulfone” refers to a group -S(O);R, in which R is alkyl, aryl, or heteroaryl.

“Substituted sulfone” refers to a group -S(O),R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

The term “keto” refers to a group —C(O)-. The term “thiocarbonyl” refers to a group — . | C(S)-- The term “carboxy” refers to a group —~C(0)-OH. “Optional” or “optionally” means that the subsequently described event or circumstance a may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

The term “compound of Formula I and Formula IT” is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, prodrugs, hydrates and polymorphs of such compounds.

Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2" stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of eachother. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(x)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the } plane of polarized light at the wavelength of the sodium D line.

The term “therapeutically effective amount” refers to that amount of a compound of

Formula I that is sufficient to effect treatment, as defined below, when administered toa mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be . determined by one of ordinary skill in the art.

The term “treatment” or “treating” means any treatment of a disease in a mammal, ‘ including: : (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (11) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms.

In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases - include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl . amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, trisubstituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines } where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. ’ Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine,

hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic and . organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, : 5 sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include : acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. ’ Nomenclature

The naming and numbering of the compounds of the invention is illustrated with a representative compound of Formula I in which R! is n-propyl, R? is n-propyl, R® is hydrogen, X is phenylene, Y is -O-(CHy), and Z is 5-(2-methoxyphenyl)-[1,2,4])-oxadiazol-3-yl, i N ~~ J 5 Ny 7 ~~ ~o

N y oe

PY / 7 ’ ’ 0% 2 >n N

J ~ which is named: 8-{4-[5-(2-methoxyphenyl)-[ 1,2,4]-0xadiazol-3-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7- trihydropurine-2,6-dione. : Synthetic Reaction Parameters }

The terms “solvent”, “inert organic solvent” or “inert solvent” mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example,

benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF ), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like]. Unless specified to the contrary, the solvents used in the reactions of the present invention . are inert organic solvents.

The term “q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to ; bring a solution to the desired volume (ie., 100%).

Synthesis of the Compounds of Formula I

The compounds of Formula I where R' and R? are the same, R® is hydrogen, and Y includes an oxygen, sulfur or nitrogen atom may be prepared as shown in Reaction Scheme I.

REACTION SCHEME 1

9 Bz Q Bz / » /

HN Ny N

Lp — 1) — . 0 N N o N N "

Rr? : (1) @

Q Bz Q Bz

Rr" / RY /

Nn | N Na N )—e =~ Jan

A N o \ >

R? , ® ANC)

Q [e Q

AN N AN N

PY | J — PY | J [o} | N fo) | N

Rr? ©) Rr?

Formula I where R? is hydrogen where Bz is benzyl, Boc is t-butyloxycarbonyl, and L is -O-, -S-, or -NH-.

Note that when R? is hydrogen, Formula I and II are the same compound as a consequence of tautomerism.

Step 1 - Preparation of Formula (2)

The compound of formula (1), which is protected at the N-7 position, is commercially available, or may be prepared by means well known in the art (see, for example, Synthetic

Communications, 20(16), 2459-2467 (1990)). The compound of formula (1) is reacted with at least two equivalents of a compound of formula R!LG, where LG is a leaving group, preferably chlorine, bromine, or iodine, in the presence of a strong base, for example sodium hydride. The reaction is carried out in a polar solvent, for example DMF, initially at a temperature of about room temperature, followed by reaction at a temperature of about 30-100°C, for example about 70°C, for about 6-24 hours. When the reaction is substantially complete, the product of formula . (2) is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel. 1t should be noted that this reaction only provides compounds of formula (2) in which R* and R? are the same. A procedure for preparing compounds of formula (2) in which R! and R2 are different is shown below in Reaction Scheme III.

A different synthesis is required for the preparation of compounds of formula (2) in which R' and/or R? are aryl or heteroaryl groups, and is shown in Reaction Scheme III.

Step 2 - Preparation of Formula (3) \ The compound of formula (2) is then halogenated at the 8-position, to give a compound of formula (3), by reaction with a halogenating agent, for example N-chlorosuccinimide, to give the 8-chloro compound of formula (3). In general, the compound of formula (2) is dissolved in an inert solvent, for example tetrahydrofuran, and N-bromosuccinimide (or N-chlorosuccinimide) is added. The reaction is carried out at a temperature of about 0-30°C, for example about room temperature, for about 1-10 hours, for example about 4 hours. When the reaction is substantially complete, the product of formula (3) is isolated by conventional means, and recrystallized.

Step 3 - Preparation of Formula (4)

The compound of formula (3) is then converted to a compound of formula (4) by reaction with an appropriately substituted boronic acid derivative in the presence of a palladium(0) complex. For example, where X is optionally substituted phenyl, the compound of formula 3) is reacted with an optionally substituted phenylboronic acid. The reaction is carried out in an inert solvent, for example toluene/ethanol, in the presence of aqueous sodium carbonate solution and tetrakis(triphenylphosphine)-palladium(0), at about reflux temperature for about 24 hours. When the reaction is substantially complete, the product of formula (4) is isolated by conventional means, for example by removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel.

Step 4 - Preparation of Formula (5) a) The benzyl protecting group of the compound of formula (4) is then replaced by Boc, to give the compound of formula (5). In general, the compound of formula (4) is dissolved in an inert solvent, for example methanol, and a hydrogenation catalyst added. The reaction is stirred under an atmosphere of hydrogen, at a temperature of about 0-30°C, for example about room temperature, for about 8-24 hours, for example about 18 hours. When the reaction is substantially complete, the catalyst is removed by filtration, and the product isolated by i conventional means. b) The product is then dissolved in an inert solvent, for example methanol, to which was ) added an excess of di t-butyldicarbonate and a hindered base, for example ethyldiisopropylamine. The mixture is refluxed for about 8-24 hours, for example about 18 hours. When the reaction is substantially complete, the catalyst is removed by filtration, and the compound of formula (5) isolated by conventional means, for example by removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel. . Step 5 - Preparation of Formula I where R? js Hydrogen

The compound of formula (5) is then converted to a compound of Formula I by reaction : with a compound of the formula Z-Y-LG, where Z and Y are as defined above and LG is a leaving group, preferably a halogen, more preferably chloro (the Boc protecting group is removed simultaneously). The reaction is carried out in the presence of a strong base, for example sodium hydride, in an inert polar solvent, preferably DMF, at a temperature of about 0- 30°C, preferably about room temperature, for about 8-24 hours, preferably about 16 hours. The

BOC protecting group is also removed in this reaction sequence. When the reaction is substantially complete, the product of Formula I where R? is hydrogen is isolated by conventional means, for example by chromatography on silica gel.

Step 5 - Preparation of Formula I where R? is other than Hydrogen

A compound of Formula I in which R® is hydrogen may be converted to a compound of

Formula I in which R? is not hydrogen by reaction with a compound of formula R3-LG, where

LG is a leaving group, preferably iodo or bromo. The reaction is carried out in the presence of a mild base, for example potassium carbonate, in an inert polar solvent, preferably DMF, at a temperature of about 30-100°C, preferably about 70°C, for about 8-24 hours, preferably about 16 hours. When the reaction is substantially complete, the product of Formula I where R is other than hydrogen is isolated by conventional means, for example by chromatography on silica gel.

Alternatively, the benzyl protecting group of formula (4) may be replaced by a trimethylsilyl-ethoxymethyl protecting group (instead of a BOC group), the subsequent removal of which can be accomplished under milder reaction conditions. In general, the product of Step 4a is dissolved in an inert solvent, preferably anhydrous DMF (100mL), and reacted with trimethylsilyl-ethoxymethyl chloride in the presence of a base, preferably potassium carbonate.

The reaction is conducted at a temperature of about 50-90°C, preferably about 70°C, for about 1- 6 days, preferably about 72 hours. When the reaction is substantially complete, the catalyst is removed by filtration, and the product isolated by conventional means, preferably flash chromatography. ] The product is then reacted with Z-Y-LG, where Z and Y are as defined above and LG is a leaving group, as shown in step 5 above. The trimethylsilyl-ethoxymethyl protecting group is removed from the resulting intermediate compound by treatment by acid in a protic solvent, preferably hydrochloric acid in ethanol, to give a compound of Formula I.

Claims (1)

1. WHAT IS CLAIMED IS:

   1. A compound of the Formula I or Formula II: Q p 0 AN oF rR N N Sw \ PN Jz PY Herz N N o N MN l. LN

   5 . Formula 1 ’ Formula IT as a free base, a pharmaceutically acceptable salt, pharmaceutically acceptable ester, prodrug, hydrate or polymorph, R' and R? are independently chosen from hydrogen, optionally substituted alkyl, or a group -D- E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; R’ is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; Xs optionally substituted arylene or heteroarylene; Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by -O-, -S- » or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to aheteroatom; and 2 is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic hsteroaryl; with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene attached to the purine ring by a carbon atom; and, with the proviso that when X is optionally substituted arylene, Z is an optionally substituted ‘25 monocyclic heteroaryl other than imidazole.

   2. The compound of claim 1, wherein: 85 AMENDED SHEET

   R' and R? are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, } R?is hydrogen; Xis optionally substituted heteroarylene; and N Y is a covalent bond or lower alkylene.

   3. The compound of claim 2, wherein X is optionally substituted pyrazolene, Y is lower alkylene, and Z is optionally substituted phenyl or optionally substituted oxadiazole.

   4. The compound of claim 3, wherein R' is lower alkyl optionally substituted by cycloalkyl and R? is hydrogen.

   5. The compound of claim 4, wherein X is optionally substituted 1,4-pyrazolene.

   :

   6. The compound of claim 5, wherein Y is -CH,- or -CH(CH3)-, and Z is optionally substituted phenyl.

   7. The compound of claim 6, wherein R' is n-propyl, X is 1,4-pyrazolene, Y is -CHy-, and Z is 3-trifluoromethylphenyl, namely 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl}-methyl} pyrazol- 4-yl)-1,3,7-trihydropurine-2,6-dione.

   8. The compound of claim 6, wherein R' is n-propyl, X is 1,4-pyrazolene, Y is -CHy-, and Z is phenyl, namely 1-propyl-8-[1-benzylpyrazol-4-yli}-1,3,7-trihydropurine-2,6-dione.

   9. The compound of claim 6, wherein R' is n-butyl, X is 1,4-pyrazolene, Y is -CHy-, and Z is 3-fluorophenyl, namely 1-butyl-8-(1-{[3-fluorophenyl}methyl}pyrazol-4-yl1)-1,3,7- trihydropurine-2,6-dione.

   10. The compound of claim 6, wherein R! is n-propyl, X is 1,4-pyrazolene, Y is : -CH(CHjs)-, and Z is phenyl, namely 1-propyl-8-[1-(phenylethyl)pyrazol-4-yi}-1,3,7- trihydropurine-2,6-dione,

   11. The compound of claim 5, wherein Y is -CH,- or -CH(CHj3)-, and Z is optionally substituted oxadiazole.

   12. The compound of claim 11, wherein R! is n-propyl, X is 1,4-pyrazolene, Y is -CHa-, and Zis 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4- . oxadiazol-3-yl) jmethyl} pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione.

   . 13. The compound of claim 11, wherein R' is n-butyl, X is 1,4-pyrazolene, Y is -CHz-, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4- chlorophenyl)(1,2,4-oxadiazol-3-yl)Jmethyl} pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6- dione. 14, The compound of claim 2, wherein R! and R? are independently lower alkyl optionally substituted by cycloalkyl.

   15. The compound of claim 14, wherein X is optionally substituted pyrazolene.

   16. The compound of claim 15, wherein X is optionally substituted 1,4-pyrazolene, Y is - CHz-, -CH(CHa)- or a covalent bond-, and Z is hydrogen or optionally substituted phenyl.

   17. The compound of claim 16, wherein R! and R? are n-propyl, Y is a covalent bond, and Z is hydrogen, namely 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.

   18. The compound of claim 16, wherein R! is sec-butyl, R? is methyl, Y is a covalent bond, and Z is hydrogen, namely 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.

   19. The compound of claim 16, wherein R! and R? are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-trifluoromethylphenyl.

   20. The compound of claim 16, wherein R' and R? are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-fluorophenyl. ” 21. The compound of claim 16, wherein R' and R? are n-propyl, Y is -CH(CH:)-, and Z is 3- trifluoromethylphenyl, namely 1,3-dipropyl-8-( 1-{[3-(trifluoromethyl)-phenyl]ethyl } pyrazol-4- ) yD-1,3,7-trihydropurine-2,6-dione.

   22. The compound of claim 16, wherein R! and R? are n-propyl, Y is methylene, and Z is 4-

   carboxyphenyl, namely 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyllpyrazol-4-y1}-1,3,7- trihydropurine-2,6-dione;

   23. The compound of claim 16, wherein R' and R? are n-propyl, Y is -CH(CO,H)-, and Z is > phenyl, namely 2-[4~(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic " acid;

   24. The compound of claim 1, wherein: R' and R? are hydrogen, optionally substituted lower alkyl, or a group -D-E, in which Dis a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, R’is hydrogen; X is optionally substituted phenylene; and Y is a covalent bond or lower alkylene in which one carbon atom can be optionally replaced by - O-, -S-, or -NH-.

   25. The compound of claim 24, wherein R' and R* are independently lower alkyl optionally substituted by cycloalkyl. :

   26. The compound of claim 25, wherein R! and R? are n-propyl and Y is -OCH;-.

   27. The compound of claim 26, wherein Z is optionally substituted oxadiazole.

   28. The compound of claim 27, wherein Z is 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3 -yl), namely 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxylphenyl}-1,3-dipropyl-1,3,7- trihydropurine-2,6-dione;

   29. The compound of claim 27, wherein Z is 5-(3-methoxyphenyl)-(1,2,4-oxadiazol-3-y1), namely 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxylphenyl}-1,3-dipropyl-1,3 ,7- trihydropurine-2,6-dione;

   30. The compound of claim 27, wherein Z is 5-(4-fluorophenyl)-(1,2,4-0xadiazol-3-y1), ' namely 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1 ,3-dipropyl-1,3,7- trihydropurine-2,6-dione;

   31. Use of a compound of the formula: 0 - 0 ANY / Rr! A N ~~ N PY | 4 or A Dz 0 N N o N \ l, l. " Formula I Formula II as a free base, a pharmaceutically acceptable salt, pharmaceutically acceptable ester, prodrug, hydrate or polymorph, wherein: R' and R® are independently chosen from hydrogen; optiomally substituted alkyl, or a group -D- E, in which DD is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot bealkoxy; R’is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; X is optionally substituted arvlene or hetervarylene; Y is a covalent bond or alkylene in which one carbon atom cam be optionally replaced by -O-, -S~- » or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatony; and Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; with the proviso that when X is optionally substituted arylene, Z is optionally substituted 89 AMENDED SHEET monocyclic heteroaryl, in the manufacture of a medicament for treating a disease state in a mammal, which disease state is alleviable by treatment with an A, adenosine receptor antagonist.

   32. The use of claim 31, wherein the disease state is chosen from atherosclerosis, angiogenesis, diabetic retinopathy, cancer, and asthma.

   33. The use of claim 31, wherein the disease state is an inflammatory gastrointestinal tract disorder. 34, The use of claim 33, wherein the inflammatory gastrointestinal tract disorder is diarrhea.

   35. The use of claim 31, wherein the disease state is a neurological disorder.

   36. The use of claim 35, wherein the neurological disorder is senile dementia, Alzheimer’s disease, or Parkinson’s disease.

   37. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1.

   38. A process for the preparation of a compound of Formula I or Formula TE 0 rR oO 1 / ‘ R RN N EN N PR xa PY | Wve o N N o N \ Lo LN Formula 1 Formula II wherein: R! and R? are independently chosen from hydrogen, optionally substituted alkyl, or a group -D- E, in which D is a covalent bond or alkylene, and B is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or opticnally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; : AMENDED SHEET

   R?is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, X is optionally substituted arylene or heteroarylene; Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by -O-, -S- “ : , or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or -COR, in which R is hydroxy, alkoxy or amino; “ with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond; with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene; and, with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl. s comprising: contacting a compound of the formula: : [o] R* NH. YX A NHR? La @n in which R', R? and R? are as defined above; with a compound of the formula Z-Y-X-CO>H, in which X, Y, and Z are as defined above.

   39. The process of claim 38, wherein R! is n-butyl, and R* and R? are hydrogen.

   40. The process of claim 39, wherein X is phenyl, Y is propylene, and Z is 1,4-pyrazolene: ; [0] “= F [3 N Ty N namely 1-[(3-fluorophenyl)methyl]pyrazole-4-carboxylic acid.

   41. The process of claim 40, wherein the reaction is carried out in the presence of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in N,N-dimethylformamide.

   42. The compound of claim 16, wherein R! is n-propyl, R? is ethyl, Y is -CH,-, and Z is 3-trifluoromethylphenyl, namely 3-ethyl-1-propyl-8-{1-[(3- trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.

   43. The compound of claim 42, wherein the compound is the free base.

   44. The compound of claim 42, wherein the compound is a pharmaceutically acceptable acid addition salt. : 45. The compound of claim 44, wherein the pharmaceutically acceptable acid addition salt is the phosphate salt.

   46. The compound of claim 44, wherein the pharmaceutically acceptable acid addition salt is the tosylate salt.

   47. A compound of the formula: 0 F 0 1 1 R Nn N R pa PY Pa PY Hea ) N N 0 N N

   I l. \e Formula I Formula IT as a free base, a pharmaceutically acceptable salt, pharmaceutically acceptable ester, prodrug, hydrate or polymorph, 92 AMENDED SHEET wherein: R' and R? are independently chosen from hydrogen; optionally substituted alkyl, or a group -D- E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot bealkoxy; Ris hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; X is optionally substituted arylene or heteroarylene; Y is a covalent bond or alkylene in which one carbon atom can be opticnally replaced by -O-, -8- , or -NH-, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; with the proviso that when X is optionally substituted arylene, Z is optionally substituted. moncyclic heteroaryl, for use in treating a disease state in a mammal, which disease state is alleviable by treatment with an A,p adenosine receptor antagonist.

   48. The compound of claim 47, wherein the disease state is chosen from atherosclerosis, angiogenesis, diabetic retinopathy, cancer, and asthma.

   49. The compound of claim 47, wherein the disease state is an inflammatory gastrointestinal tract disorder.

   50. The compound of claim 49, wherein the inflammatory gastrointestinal tract disorder is diarrhea.

   51. The compound of claim 47, wherein the disease state is a neurological disorder.

   52. The compound of claim 51, wherein the neurological disorder is senile dementia, Alzheimer’s disease, or Parkinson’s disease.

   53. A compound according to either one of claims 1 or 47, substantially as herein described and exemplified.

   54. A process according to claim 38, substantially as herein described and exemplified. 92A AMENDED SHEET

   H {

   55. A pharmaceutical composition according to claim 37, substantially as herein described and exemplified.

   56. Use according to claim 31, substantially as herein described and exemplified. 92B AMENDED SHEET