Imidazo-heterobicycles as factor Xa inhibitors

The present application describes imidazo-heterobicycles of formulas I and III: or pharmaceutically acceptable salt or prodrug forms thereof. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

FIELD OF THE INVENTION

This invention relates generally to imidazo-heterobicycles, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO94/20460 describes angiotensin II compounds of the following formula:

wherein X can be a number of substituents and Het can be a nitrogen-containing heterobicycle. However, WO94/20460 does not suggest Factor Xa inhibition or exemplify compounds like those of the present invention.

WO96/12720 describes phosphodiesterase type IV and TNF production inhibitors of the following formula:

wherein X can be oxygen and R 2 and R 3 can a number of substituents including heterocycle, heterocycloalkyl, and phenyl. However, the presently claimed compounds do not correspond to the compounds of WO96/12720. Furthermore, WO96/12720 does not suggest Factor Xa inhibition.

WO98/52948 describes inhibitors of ceramide-mediated signal transduction. One of the types of inhibitors described is of the following formula:

wherein Y 1 can be N R 6 , R 6 can be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl and R 1 can be a substituted aryl group. WO98/52948 does not mention factor Xa inhibition or show compounds like those of the present invention.

wherein A is 2-3 carbon atoms, X can be 0, and R 1 and R 3 can be substituted or unsubstituted aromatic groups. Neither of these patents, however, exemplify compounds of the present invention.

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca 2 and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel imidazo-heterobicycles that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide novel bicyclic compounds for use in therapy.

It is another object of the present invention to provide the use of novel bicyclic compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed bicyclic compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

1 Thus, in an embodiment, the present invention provides a novel compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is a group of formula IIa or IIb:

ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered non-aromatic ring consisting of carbon atoms, 0-1 double bonds, and from 0-2 N, and D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;

alternatively, ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered aromatic system consisting of carbon atoms and from 0-2 heteroatoms selected from the group consisting of N, O, and S, and D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;

E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 0-1 R;

alternatively, the bridging portion of ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with R a and R b ;

alternatively, R a and R b combine to form methylenedioxy or ethylenedioxy;

A is selected from:

5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4 ;

B is selected from:

Y is selected from:

5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4a ;

R 1d is selected from C 3-6 carbocycle substituted with 0-2 R 4a , and 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4a , provided that R 1d forms other than an N N, N S, or N O bond;

R 2 , at each occurrence, is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 carbocycle substituted with 0-2 R 4b , a C 3-6 carbocyclic-CH 2 -residue substituted with 0-2 R 4b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

R 2a , at each occurrence, is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 carbocycle substituted with 0-2 R 4b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

R 2b , at each occurrence, is selected from CF 3 , C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocycle substituted with 0-2 R 4b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

R 2c , at each occurrence, is selected from CF 3 , OH, C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

alternatively, R 2 and R 2a , together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R 4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R 3 , at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;

R 3a , at each occurrence, is selected from H, C 1-4 alkyl, benzyl, and phenyl;

R 3b , at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;

R 3c , at each occurrence, is selected from C 1-4 alkyl, benzyl, and phenyl;

alternatively, one R 4 is a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, one R 4a is phenyl substituted with 0-1 R 5 or a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R 5 ;

alternatively, R 7 and R 8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

n, at each occurrence, is selected from 0, 1, 2, and 3;

p, at each occurrence, is selected from 0, 1, and 2;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0, 1, 2, and 3.

2 In a preferred embodiment, the present invention provides a novel compound, wherein:

G is selected from the group:

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4 ;

B is Y or X-Y;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems that are substituted with 0-2 R 4a ;

alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.

3 In another preferred embodiment, the present invention provides a novel compound, wherein:

G is selected from the group:

S is 0.

4 In another preferred embodiment, the present invention provides a novel compound, wherein:

G is selected from:

5 In another preferred embodiment, the present invention provides a novel compound, wherein;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R 4 ; and,

R 2a , at each occurrence, is H or CH 3 ;

alternatively, R 2 and R 2a , together with the atom to which they are attached, combine to form pyrrolidine substituted with 0-2 R 4b ;

R 4b , at each occurrence, is selected from H, CH 3 , and OH;

r, at each occurrence, is selected from 0, 1, and 2.

6 In another preferred embodiment, the present invention provides a novel compound, wherein;

7 In another preferred embodiment, the present invention provides a novel compound selected from:

or a pharmaceutically acceptable salt form thereof.

8 In another embodiment, the present invention provides a novel compound of formula III:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

provided that ring M is other than:

alternatively, M 1 is C(O), M 2 is N, and the remainder of ring M is S(O) 2 ;

M 3 is -A-B;

G is a group of formula IIa or IIb:

ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered non-aromatic ring consisting of carbon atoms, 0-1 double bonds, and from 0-2 N, and D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;

alternatively, ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered aromatic system consisting of carbon atoms and from 0-2 heteroatoms selected from the group consisting of N, O, and S, and D is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;

E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 0-1 R;

alternatively, the bridging portion of ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with R a and R b ;

alternatively, R a and R b combine to form methylenedioxy or ethylenedioxy;

A is selected from:

5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4 ;

B is selected from:

Y is selected from:

5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N,

O, and S substituted with 0-2 R 4a ;

R 1d is selected from C 3-6 carbocycle substituted with 0-2 R 4a , and 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4a , provided that R 1d forms other than an N N, N S, or N-0 bond;

R 2 , at each occurrence, is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 carbocycle substituted with 0-2 R 4b , a C 3-6 carbocyclic-CH 2 -residue substituted with 0-2 R 4b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

R 2a , at each occurrence, is selected from H, CF 3 , C 1-6 alkyl, benzyl, C 3-6 carbocycle substituted with 0-2 R 4b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

R 2b , at each occurrence, is selected from CF 3 , C 1-4 alkoxy, C 1-6 alkyl, benzyl, C 3-6 carbocycle substituted with 0-2 R 4b , and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

R 2c , at each occurrence, is selected from CF 3 , OH, C 1-4 alkoxy, C 16 alkyl, benzyl, C 3-6 carbocyclic residue substituted with 0-2 R 4b , and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 4b ;

alternatively, R 2 and R 2a , together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R 4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R 3 , at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;

R 3a , at each occurrence, is selected from H, C 1-4 alkyl, benzyl, and phenyl;

R 3b , at each occurrence, is selected from H, C 1-4 alkyl, and phenyl;

R 3c , at each occurrence, is selected from C 1-4 alkyl, benzyl, and phenyl;

alternatively, one R 4 is a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, one R 4a is phenyl substituted with 0-1 R 5 or a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R 5 ;

alternatively, R 7 and R 8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

n, at each occurrence, is selected from 0, 1, 2, and 3;

p, at each occurrence, is selected from 0, 1, and 2;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0, 1, 2, and 3.

9 In another preferred embodiment, the present invention provides a novel compound, wherein:

ring M is substituted with 0-2 R 3 and is selected from the group:

G is selected from the group:

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R 4 ;

B is Y or X-Y;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems that are substituted with 0-2 R 4a ;

alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.

10 In another preferred embodiment, the present invention provides a novel compound, wherein:

ring M is substituted with 0-2 R 3 and is selected from the group:

G is selected from the group:

s is 0.

11 In another preferred embodiment, the present invention provides a novel compound, wherein:

ring M is substituted with 0-1 R 3 and is selected from the group:

G is selected from:

12 In another preferred embodiment, the present invention provides a novel compound, wherein;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R 4 ; and,

R 2a , at each occurrence, is H or CH 3 ;

alternatively, R 2 and R 2a , together with the atom to which they are attached, combine to form pyrrolidine substituted with 0-2 R 4b ;

R 4b , at each occurrence, is selected from H, CH 3 , and OH;

r, at each occurrence, is selected from 0, 1, and 2.

13 In another embodiment, the present invention provides a novel compound, wherein;

14 In another preferred embodiment, the present invention provides a novel compound selected from:

or a pharmaceutically acceptable salt form thereof.

15 In another preferred embodiment, the present invention provides a novel compound selected from:

or a pharmaceutically acceptable salt form thereof.

16 In another preferred embodiment, the present invention provides a novel compound selected from:

or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides novel compounds as described above for use in therapy.

In another embodiment, the present invention provides the use of novel compounds as described above for the manufacture of a medicament for the treatment of a thromboembolic disorder.

Definitions

When any variable (e.g., R 6 ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R 6 , then said group may optionally be substituted with up to two R 6 groups and R 6 at each occurrence is selected independently from the definition of R 6 . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C 1-10 alkyl, is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example C v F w where v 1 to 3 and w 1 to (2v 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C 1-10 alkoxy, is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C 3-7 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , and C 7 cycloalkyl groups. Alkenyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C 2-10 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkenyl groups. Alkynyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C 2-10 Alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 alkynyl groups.

Halo or halogen as used herein refers to fluoro, chloro, bromo, and iodo; and counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, the term heterocycle or heterocyclic system is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1. As used herein, the term aromatic heterocyclic system or heteroaryl is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and 0 atoms in the aromatic heterocycle is not more than 1.

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc. . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. Preferred prodrugs are amidine prodrugs wherein D is C( NR 7 )NH 2 or its tautomer C( NH)NHR 7 and R 7 is selected from OH, C 1-4 alkoxy, C 6-10 aryloxy, C 1-4 alkoxycarbonyl, C 6-10 aryloxycarbonyl, C 6-10 arylmethylcarbonyl, C 1-4 alkylcarbonyloxy C 1-4 alkoxycarbonyl, and C 6-10 arylcarbonyloxy C 1-4 alkoxycarbonyl. More preferred prodrugs are where R 7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using substituted is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., O) group, then 2 hydrogens on the atom are replaced.

As used herein, treating or treatment cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

Therapeutically effective amount is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect (in this case, inhibition of factor Xa) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts ( Protective Groups In Organic Synthesis , Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

The compounds of the present invention represented by Formula I consist of a group G-(CH 2 ) s - and a group -A-B attached to a 5,6 - or 5,7 -heterobicyclic core structure of varying composition. The five-membered ring is imidazole and this ring can be fused to a variety of six- or seven membered rings including but not limited to piperidinone, pyridinone, pyrimidinone, pyrimidinedione, pyranone, diazepinone, diazepinedione. The following discussion and schemes will describe methods for the syntheses of the heterobicyclic cores and attachment to the groups G-(CH 2 )S- and -A-B .

Bicyclic compounds of the present invention in which the five membered ring is imidazole and the G-containing group is attached to a nitrogen atom and M 3 is attached through a C-N linkage can be prepared as shown in WO00/39131, specifically Scheme XXI therein.

Bicyclic compounds of the present invention in which the five membered ring is imidazole and the G-containing group is attached to a nitrogen atom and M 3 is attached through a C C linkage can be prepared as shown in Scheme I.

3-Hydroxy-2-nitro-2-cyclohexen-1-one I (Krebs, E. P.; et al. Helv. Chim. Acta 1979, 62, 497-506) upon nitro reduction and acylation with acetic formic anhydride gives formamide II which is then cyclized to a 2-substituted 3,5,6,7-tetrahydro-benzimidazol-4-one III in the presence of formic acid and R 1a carboxamide. Imidazole alkylation (s>0) or arylation (s 0) is accomplished using standard methodology to give IV. Introduction of M 3 is performed using enolate arylation conditions (Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108-11109) to furnish V.

Scheme II describes synthesis of VII, the 5,6-dihydro version of V, depending on whether the G-group is directly attached (s 0) to the imidazole or not (s>0). For the directly attached G-group (s 0), one begins from V and bromination at C-7 followed by a base assisted elimination and isomerization of the double bond gives VI. For non-direct G-group attachment (s>0) one begins from 3-bromo-6-nitro-o-anisidine. After a Pd 0 catalyzed C C cross-coupling with boronic acid M 3 to give IX, an alkylation of aniline IX would afford X. Imidazole ring formation could be completed using standard conditions followed by methyl ether deprotection to give VII.

Scheme III shows the synthesis of imidazo-piperdine XIV. Beginning from chloro-nitro-imidazole X (Sarasin, J. Helv. Chim. Acta 1924, 7, 713) and through standard synthetic manipulations (Tennant, G. J. Chem Soc., Perkin Trans. 1, 1999, 629-640) aldehyde XI is made. Upon nitro group reduction and condensation hydroxyl-amine XII is constructed. Alkylation of nitrogen is completed with bromide Z 2 -Br to arrive at XIV.

Scheme IV demonstrates how compound XIX can be made from 2,4-dimethoxy-6-nitroaniline XV (Gengnagel, K.; et al. Eur. Pat. Appl. ( 1982) EP 54228 Al) through a series of steps similar to those shown in Scheme II.

Scheme V outlines the conversion of XIII to XXI via MnO 2 oxidation followed by alkylation. Alternatively, XIV could be directly oxidized to XXIV.

Scheme VI provides for a route to imidazopyridinones such as XXIX. Following methodology similar to that outlined in Scheme III, one could start from a compound such as X to give XXV. Using reported methodology (Tennant, G. J. Chem Soc., Perkin Trans. 1, 1999, 629-640) compound XXVI could be made via alkylation of XXV. Reduction and ring closure yields XXVII which could be alkylated to afford XXVIII.

Scheme VII provides for a route to compound XXXIV, an imidazo 4,5b azepinedione. From compound X through steps described earlier one could make XXX. Acylation and teatment with base will induce cyclization to both XXXII and XXXIII. Reduction of the alcohol and introduction of M 3 is performed using enolate arylation conditions (Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108-11109) to furnish XXXIV.

The A-B moieties can be prepared by methods known to those of skill in the art. The following publications, the contents of which are incorporated herein by reference, describe and exemplify means of preparing A-B moieties: WO97/23212, WO97/30971, WO97/38984, WO98/06694, WO98/01428, WO98/28269, WO98/28282, WO99/12903, WO98/57934, WO98/57937, WO98/57951, WO99/32454, WO99/50255, WO00/39131, WO00/38683, WO00/39102, WO01/05784, and WO00/39108.

EXAMPLES

Proton NMR spectra were obtained on a Bruker AC 300 or Bruker AMX 500 spectrometer and were referenced to tetramethylsilane. Mass spectra were obtained on a Shimadzu QP-5000 mass spectrometer (CI or EI) or Perkin Elmer Sciex 100 atmospheric pressure ionization (API) spectrometer. HPLC analyses were obtained using a Rainin Dynamax C18 column with UV detection at 230 nm using a standard gradient program.

The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, in Tables 1 and 2, example 1 is intended to be paired with each of the formulae.

The following nomenclature is intended for group A in the following tables.

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term thromboembolic disorders as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K i .

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K m , for substrate hydrolysis was determined at 25 C. using the method of Lineweaver and Burk. Values of K i were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate K i values:

( v o v s )/ v s I /( K i (1 S/K m ))

v o is the velocity of the control in the absence of inhibitor;

v s is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K i is the dissociation constant of the enzyme: inhibitor complex;

S is the concentration of substrate;

K m is the Michaelis constant.

Compounds tested in the above assay are considered to be active if they exhibit a K i of 10 M. Preferred compounds of the present invention have K i 's of 1 M. More preferred compounds of the present invention have K i 's of 0.1 M. Even more preferred compounds of the present invention have K i 's of 0.01 M. Still more preferred compounds of the present invention have K i 's of <0.001 M.

The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing that contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 1990, 265, 18289-18297, herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm that arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K i of less than 10 m, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. By therapeutically effective amount it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By administered in combination or combination therapy it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences , Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.