AU2007202110B2

AU2007202110B2 - 1-aroyl-piperidinyl benzamidines

Info

Publication number: AU2007202110B2
Application number: AU2007202110A
Authority: AU
Inventors: Peter C. Astles; Paul R. Eastwood; Yong Gong; Julian Levell; Heinz Pauls
Original assignee: Aventisub LLC
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 2000-04-27
Filing date: 2007-05-11
Publication date: 2008-10-16
Anticipated expiration: 2021-04-27
Also published as: AU2007202110A1

Description

P001 Section 29 Regulation 3.2(2)

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: 1-aroyl-piperidinyl benzamidines The following statement is a full description of this invention, including the best method of performing it known to us: WCO 01/81310 P'TIi1 n /110 Ic 1-AROYL-PIPERIDINYL BENZAMIDINES Field of the Invention The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, the compounds of formula I exhibit Factor Xa inhibitory activity and tryptase inhibitory activity. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use for treating a patient.suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa or an inhibitor of tryptase.

Factor Xa is the penuitimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) O0 are inhibited by compounds of formula I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin IL. Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following WO 01/81310 PCT/US01/13810 -2- O abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to Sa higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems. The indications discussed above include some, but not all, of the possible clinical S situations where anticoagulant therapy is warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.

O Tryptase is stored in mast cell secretory granules and is the major secretory protease of human 10 mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of 0 vasodilating and bronchorelaxing neuropeptides (Caughey, et al., J. Pharmacol. Exp. Ther. 244:133- 137 (1988); Franconi, et al., J. Pharmacol. Exp. Ther. 248:947-951 (1988); and Tam, et al., Am. J.

Respir. Cell Mol. Biol. 3:27-32 (1990)) and modulation of bronchial responsiveness to histamine (see Sekizawa, et al., J. Clin. Invest. 83:175-179 (1989)). As a result, tryptase inhibitors may be useful as anti-inflammatory agents (K Rice, PA. Sprengler, Current Opinion in Drug Discovery and Development (1999) 2(5):463-474) particularly in the treatment of chronic asthma Zhang, H.

Timmerman, Mediators Inflamm (1997) 112:311-317) and may also be useful in treating or preventing allergic rhinitis J. Wilson et al, Clin. Exp. Allergy (1998) 28:220-227), inflammatory bowel disease Bischoff et al, Histopathology (1996) 28:1-13), psoriasis Naukkarinen et al, Arch. Dermatol.

Res. (1993) 285:341-346), conjunctivitis (A.A.Irani et al, J. Allergy Clin. Immunol. (1990) 86: 34-40), atopic dermatitis Jarvikallio et al, Br. J. Dermatol. (1997) 136:871-877), rheumatoid arthritis (L.C Tetlow et al, Ann. Rheum. Dis. (1998) 54:549-555), osteoarthritis Buckley et al, J. Pathol.

(1998) 186:67-74), gouty arthritis, rheumatoid spondylitis, and diseases of joint cartilage destruction.

In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung diseases (Ruoss et al., J. Clin.

Invest. 88:493-499 (1991)). Therefore, tryptase inhibitors may be useful in treating or preventing fibrotic conditions Cairns, A.F. Walls, J. Clin. Invest. (1997) 99:1313-1321) for example, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.

Additionally, tryptase inhibitors may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture Jeziorska et al, J. Pathol.

(1997) 182:115-122). Tryptase has also been discovered to activate prostromelysin which in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively. Therefore, tryptase inhibitors could be useful in the treatment or prevention of arthritis, periodontal disease, diabetic retinopathy, and tumor growth (WJ. Beil et al, Exp. Hematol. (1198) 26:158-169). Also, tryptase inhibitors may be useful in the treatment of anaphylaxis Schwarz et WO 01/81310 PCTIUS01/13810 -3- 0 O al, J. Clin. Invest. (1995) 96:2702-2710), multiple sclerosis Steinhoff et al, Nat. Med. Y.) (2000) 6(2):151-158), peptic ulcers and syncytial viral infections.

Mast cell mediated inflammatory conditions, in particular asthma, are a growing public health concern. Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation. Leukocytes containing IgE receptors, notably mast cells and basophils, are present in the epithelium and underlying smooth muscle tissues of bronchi.

SThese leukocytes initially become activated by binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells S0 leads to the release of proteoglycans, peroxidase, arylsulfatase B, tryptase and chymase, which results 0in bronchiole constriction.

SUMMARY OF THE INVENTION This invention is directed to a compound of formula I: R (R2) Xa Xb N wherein: Z is a carbon or nitrogen atom; 'J is a 4 to 7-membered azaheterocyclyl or a 4 to 7-membered azaheterocyclenyl group; is a single or double bond, provided that when Z is a nitrogen atom then is a single bond; O is an aryl group, a monocyclic heteroaryl group, or a bicyclic azaheteroaryl group which includes a first proximal ring that is attached to the moiety and a ring distal to said first ring, said distal ring including at least one nitrogen atom R' is hydrogen, -CH 2

OR'

2

-CH

2

SR'

2 -CO2R" 3 or-CONR' 3

R

3

R

2 is hydrogen, alkyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, WO 01/81310 PCT[USOI/13810 -4alkoxycarbonyL, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alcylsulinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, aryltio, heteroarylthio, arallcylthio, heteroaralkylthio, Y 1

Y

2 Y IY 2 N-alkyl-, Y 1

Y

2 NCO- or Y 1

Y

2 NSO2-; WR is cycloalkyl, cycloalkenyl, heterocyclyl, beterocyclenyl, fused arylcycloalcyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused aryiheterocyclyl, fused heteroaryiheterocyclyL, fused arylbeterocyclenyl, fused heteroaryiheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused beterocyclenylaryl, heteroaryl, fused cycloalkyiheteroaryl, fused cycloalkenyiheteroaryl, fused heterocyclenyiheteroaryl, fused heterocyclyiheteroaryl; 0Xa, Xb Xc are independently selected from hydrogen, RWRN-, (hydroxy)HN-, (alkoxy)HN-, RWO-, ci

R

8

RO

R

4

R

5 NCO-, RNSO 2

R

6 CO-, halo, cyano, nitro, R 7 (O)C(C11 2 and H 2 N and when Q is a bicyclic heteroaryl group, then Xr is a substituent that is at the alpha position with respect to a nitrogen atom of said distal ring of®@ and Xr is selected from the group consisting of HK hydroxy and H 2 (optionally substituted lower alkyl)HN (hydroxy)HN-, and (alkoxy)HN-;

W

4 and W 5 are independently H or optionally substituted lower alkyl, or one of R 4 and R 5 is H and the other of RW and W 5 is R7(O)CCH 2 or lower acyl;

R

6 i H, optionally substituted lower alkyl, lower acyl or R?(O)CCH2-; R7 is H, optionally substituted lower alkyl, alkoxy or hydroxy; R8 and R 9 taken together are =NR' 0

R

10 is hydrogen, R 11 0 2 HO-, cyano, R 11 C0-, HCO-, lower alkcyl, nitro, or Y2is alkyl, aralkyl, or heteroaralkyl; R1 2 is hydrogen, lower aiy, aryl(lower alkyl), heteroaryl(lower alkyl), lower acyl, aroyl, or beteraroyl; R 1 3 is hydrogen or lower alkyl; YI and Y 2 are independently hyd rogen, alkyl, aryl, and aralkyl, or where the substituent is Y IY 2 N- or

Y'Y

2 N.alcyl. then one of YI and y 2 is acyl or aroyl and the other of YI and Y 2 is hydrogen, alkyl, aryl, or aralkyl; and Y2' are independently hydrogen or alkyl; n is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.

According to a preferred aspect of the invention there is provided a compound of formula I: wherein, Z is CH or N; is a single or double bond, provided that when Z is nitrogen atom, then is a single bond;

R

3 is phenyl that is optionally substituted with one or two ring system substituents which may be the same or different, or pyridyl or thienyl that is optionally substituted by one or two ring system substituents which may be the same or different, and wherein, the pyridyl nitrogen atom is optionally oxidized to the corresponding N-oxide; and ring system substituents are selected from the group consisting of, F,O NH 2 0 N 0 NH2

NH

2 NMe 2

O=S"

6 N H 2 0 2

N

S

N /N N F

N

0 NH 2 0 NH, NH2

-N

0 NH 2 s- NH 2 0 0=3, /I NH 202 0 0 2

AN

0 NH 2 0 NH2 In N I02 N

N

IS

N Nk

I

F N /I N N F

N

S

NJ/

F W~e no a hamaeuialy ccpabe al heeo, n Nieteef hdaeteefo aslaeteef WO 01/81310 PCTIUS01113810 DETAILED DESCRIPTION OF THE INVENTION As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings: Definitions "Patient" includes both human and other mammals.

S"Effective amount" is meant to describe an amount of compound of the present invention effective in inhibiting Factor Xa or tryptase and thus producing the desired therapeutic effect.

S"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having t0 about I to about 15 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms Sin the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl" means about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted by one or more halo, cycloalkyl or cycloalkenyl. Representative alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, npentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 0t carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted by one or more halo. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Representative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and the like.

WO 01/81310 PCT[US01/13810 -6- "Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carboncarbon double bond. Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is O norbomylenyl.

S"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system of about 3 to 0 about ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the 10 ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and Swhich contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2pyrazolinyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like "Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.

Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl is optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

"Aryl" means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.

Representative aryl groups include phenyl and naphthyl.

WO 01/81310 PCT[US01/13810 -7- 0 O "Heteroaryl" means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" is optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the Scorresponding N-oxide. Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, Simidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.

"Fused arylcycloalkenyl" means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. Representative fused arylcycloalkenyl include 1,2-dihydronaphthylene, indene, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkenylaryl" means a radical derived from a fused arylcycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylcycloalkyl" means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. Representative fused arylcycloalkyl includes 1,2,3,4tetrahydronaphthyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylaryl" means a radical derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkylaryl are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylheterocyclenyl" means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused WO 01/81310 PCT[US01/13810 -8arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system 1 5 substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is optionally oxidized to the corresponding 0 N-oxide, S-oxide or S,S-dioxide. Representative fused arylheterocyclenyl include 3H-indolinyl, 1H-2oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2- O dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is 10 through a non-aromatic carbon atom.

"Fused heterocyclenylaryl" means a radical derived from a fused arylheterocyclenyl as defined

C

herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused arylheterocyclyl" means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative preferred fused arylheterocyclyl ring systems include phthalimide, 1,4-benzodioxane, indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenz(f]isoindolyl, 1,2,3,4-tetrahydrobenz[g]isoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclylaryl" means a radical derived from a fused aryheterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylcycloalkenyl" means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion.

Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl and the cycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused WO 01/81310 PCT/US01/13810 -9heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkenylheteroaryl" means a radical derived from a fused heteroarylcycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroaylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.

.0 "Fused heteroarylcycloalkyl" means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.

The fused heteroarylcycloalkyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro- H-benzimidazolyl, !0 4,5,6,7-tetrahydrobenzoxazolyl, 1H-4-oxa-1,5-diazanaphthalen-2-onyl, 1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused cycloalkylheteroaryl" means a radical derived from a fused heteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.

"Fused heteroarylheterocyclenyl" means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion.

Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl poition of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

Representative fused heteroarylheterocyclenyl include 7,8-dihydro[1,7]naphthyridinyl, WO 01/81310 PCTfUS01/13810 I ,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-C]pyfldy1, 1 ,2-dihydro- naphthyridinyl. I ,2-dihydro-1,6-naphthyridinyl, I ,2-dihydro-l1,7-naphthyridinyL, 1 ,2-diydro- 1,8naphthyridinyL, 1 ,2-dihydro-2,6-naphthyridinyL, and the like, in which the bond to the parent moiety is through a non aromatic carbon atom.

"Fused heterocyclenylheteroaryl" means a radical derived from a fuised heteroaryiheterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroaryiheterocyclenyL, except that the bond to the parent moiety is through an aromatic carbon 0 atom.

"Fused heteroaryiheterocyclyl" means a iradical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion.

Preferred fused heteroaryiheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroaryiheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroaryllieterocyclyl is optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroaryiheterocyclyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur Z0 atom of the heterocyclyl portion of the fused heteroaryiheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroaryiheterocyclyl include 2,3-dihydro- III pyrrol[3 ,4-b]quinolin-2-yl, I ,2,3,4-tetrahydrobenz [bjj[1 ,7]naphthyridin-2-yL, 1,2,3,4tetrahydrobenz ,6]naphthyridin-2-yi, 1 ,2,3,4-tetz-ahydro-911-pyrido[3,4-b]ifldol-2yl, 1,2,3,4tetahydro-9H-pyridoII4,3-b]indol-2yl, 2,3,-dihydro- 1H-pyrrolo[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, 1 H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yi, I H-2,3,4,5-tetrahydroazepino[4,5-b~indol-2 yI, 5,6,7,8-tet-ahydro[1 ,7]napthyridinyl, I ,2,3,4-tetrhydro[2,7]naphthyridyl, 2,3-dibydro[1 ,4]dioxino[2,3-b~pyridyl, 2,3-dihydro[1 ,4]dioxino[2,3-b]pyridyl, 3,4-dihydro-2H- 1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo(4,5-c~pyridy1, 6,7-dihydro[5,8]diatzanaphthaleflyl, 1 ,2,3,4-tetrahydro[l napthyridinyl, 1 ,2,3,4-tetrahydro[ 1,6]napthyridinyl, 1 ,2,3,4-tetrahydro[1 ,7]napthyridinyl, 1,2,3,4tetrahydro[1,8]napthyridinyl, 1,2,3,4-tetrahydro[2,6]napthyridinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.

"Fused heterocyclyiheteroaryl" means a radical derived from a fused heteroaryiheterocyclyl as defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclylheteroaryl are as described herein for fused heteraryiheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.

WO 01/81310 PCTfUS01/13810 -11- "Aralkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described.

Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2phenethyl and naphthlenemethyl.

"Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl moiety. Representative aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl.

"Aralcynyl" means an aryl-alkynyl- group in which the aryl and alkynyl are as previously described. Preferred aralkynyls contain a lower alkynyl moiety. Representative aralkynyl groups include phenacetylenyl and naphthylacetylenyl.

0 "Heteroaralkyl" means an heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl moiety. Representative aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl.

"Heteroaralkenyl" means an heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl moiety. Representative heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl.

"Heteroaralkynyl" means an heteroaryl-alkynyl- group in which the heteroaryl and alklynyl are as previously described. Preferred heteroaralynyls contain a lower alkynyl moiety. Representative heteroaralkynyl groups include pyrid-3-ylacetylenyl and quinolin-3-ylacetylenyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred !0 hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2hydroxyethyl.

"Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyls contain a lower ailcyl. Representative acyl groups incluide formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

"Aroyl" means an aryl-CO- group in which the aryl group is as previously described.

Representative groups include benzoyl and 1- and 2-naphthoyl.

"Heteroaroyl" means a heteroaryl-CO- group in which the heteroaryl group is as previously described. Representative groups include nicotinoyl and pyrrol-2-ylcarbonyl and 1- and 2-naphthoyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described.

Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described.

Representative aryloxy groups include phenoxy and naphthoxy.

"Aralkyloxy" means an aralkyl-O- group in which-the aralkyl groups is as previously described. Representative aralkyloxy groups include benzyloxy and WO 01181310 PCT[US01/13810 -12- 1- or 2-naphthalenemethoxy.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described.

Representative alkylthio9 groups include methylthio, ethylthio, i-propylthio and heptylthio.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described.

Representative arylthio groups include phenylthio and naphthylthio.

"Arallcylthio" means an aralkyl-S- group in which the aralkyl group is as previously described.

A representative aralkylthio group is benzylthio.

yI 2- means a substituted or unsubstituted amino group, wherein Y I and y 2 are independently hydrogen, alkyl, aryl, or aralkyl, or one of YI and Y 2 is acyl or aroyl and the other of c-i YI and y 2 is hydrogen, alkyl aryl, and aralkyl. Representative groups include amino (H2N-), methylanino, ethylmethylamino, dimethylamino and diethylamino.

"Alkoxycarbonyl" means an alkyl-O-CQ- group. Representativ e alkoxycarbonyl groups include niethoxy- and ethoxycarbonyl.

"Aryloxycarbonyl" means an aryl-O-CO- group. Representative aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-CO- group. A representative aralkoxycarbonyl group is benzyloxycarbonyl.

"Y IY 2 NCO-" means a substituted or unsubstituted carbamoyl group, wherein Y I and y 2 are independently hydrogen, alkyl, aryl, or aralkyl. Representative groups are carbamoyl (H2NCO-) and dimethylaminocarbamoyl (Me2NCO-).

"y 1 y 2 NSO2-' means a substituted or unsubstituted sulfanioyl group, wherein Y 1 and Y 2 are independently hydrogen, alkyl, aryl, or aralkyl. Representative groups are sulfarnoyl (H2NSO2-) and diniethylsulfamoyl (Me2NSO2-).

"Allcylsulfonyl' means an alkyl-S02- group. Preferred groups are those in which the alkyl group is lower alkcyl.

"Alkylsulfinyl" means an alkyl-SO- group. Preferred groups are those in which the alkyl group is lower alkyl.

"Arylsulfonyl" means an aryl-S02- group.

"Arylsulfinyl" means an arylbSO- group.

"Halo" means fluoro, chioro, bromo, or iodo. Preferred are fluoro, chloro or bromno, and more preferred are fluoro or chioro.

"Ring system substituent! 'means a substituent attached which optionally replaces hydrogen on an aromatic or non-aromatic ring system. Ring system substituents are selected from the group consisting of aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, WO 01/81310 PCT/US01/13810 -13- Oheteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo,.

heteroaryldiazo, amidino, Y 1

Y

2

Y

1 y 2 N-alkyl-, Y 1

Y

2 NCO- or Y 1 y 2 NS02-, wherein Y 1 and Y 2 are independently hydrogen, alkyl, aryl, aralkyl, or Yly 2 N-alkyl-; or where the substituent is Y 1 y 2

N-

S or Y 1 y 2 N-alkyl- then one of Y 1 and Y 2 is acyl or aroyl and the other ofY 1 and Y 2 is hydrogen, alkyl, aryl, or aralkyl. When a ring system is saturated or partially saturated, the "ring system substituent" further comprises methylene (H 2 oxo and thioxo 0 "Solvate" means a physical association of a compound of this invention with one or more c solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.

"Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule(s) is/are

H

2 0.

"Prodrug" means a form of the compound of formula I suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for their intended use, including ketal, ester and zwitterionic forms. A prodrug is transformed in vivo to yield the parent 0 compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S.

Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

Preferred Embodiments A preferred embodiment of the invention is a method for treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound of formula I.

Another preferred embodiment of the invention is a method for preventing and treating an inflammatory diseases associated with tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound of formula I.

Another preferred embodiment of the invention is a method for preventing and treating late phase bronchoconstriction associated with chronic asthma comprising administering to said patient a pharmaceutically effective amount of a compound of formula I.

WO 01/81310 PCTfUS01/13810 -14- Another preferred embodiment of the invention is a method for treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound of formula I, wherein said disease state is selected from the group consisting of immunomediated inflammatory disorders associated with tryptase activity, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, rheumatoid spondylitis, diseases of joint cartilage destruction, ocular conjunctivitis, vernal conjunctivis, inflammatory bowel disease, asthma, allergic rhinitis, and interstitial lung diseases.

Another preferred embodiment of the invention is a method for treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound of formula I, wherein said disease state is selected from the group consisting offibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, and various dermatological conditions, for example, atopic dermatitis and psoriasis.

Another preferred embodiment of the invention is a method for treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to said patient a pharmaceutically effective amount of a compound of formula I, wherein said disease state is selected from the group consisting of myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture; as well as periodontal disease, diabetic retinopathy, tumor growth, anaphylaxis, multiple sclerosis, peptic ulcers, and syncytial viral infections.

Another preferred embodiment of the invention is a method of inhibiting tryptase activity comprising contacting a tryptase inhibitory amount of a compound of formula I with a composition containing tryptase.

Another preferred embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound of formula I and a pharmaceutically acceptable carrier.

Another preferred embodiment of the invention is a method of treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising administering to a patient, in need thereof, a compound of formula I or a pharmaceutically acceptable salt thereof, and optionally at least one compound selected from the group consisting of a P-adrenergic agonist compound, an anti-inflammatory corticosteroid compound, an anticholinergics compound, and an antiinflammatory compound, or a pharmaceutically acceptable salt thereof, wherein said 3-adrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, formoterol, fenoterol, and prenaline; said anti-inflammatory corticosteroid compound is selected from the group consisting of beclomethasone, triamcinolone, flurisolide, and dexamethasone; said anticholinergics compound is ipratropium bromide; and said anti-inflammatory compound is selected from the group consiting of sodium cromoglycate and nedocromil sodium.

WO 01/81310 PCT/US01/13810

O

SAnother further preferred embodiment of the invention is a pharmaceutical composition comprising a compound of formula I, and one or more of the following: a P-adrenergic agonist compound, an anti-inflammatory corticosteroid compound, an anticholinergics compound, or an antiinflammatory compound, and a pharmaceutically acceptable carrier.

Another further preferred embodiment of the invention is an aerosol composition for treating a patient suffering from a disease state capable of being modulated by inhibiting tryptase activity comprising a compound of formula I and an aerosolized pharmaceutically acceptable carrier or solution or dry powder.

SAnother further preferred embodiment of the invention is a pharmaceutical kit for treating or 0 preventing a a disease state capable of being modulated by inhibiting tryptase activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound of formula I and at least another of said containers contains one or more compounds selected from the group consisting of a (3-adrenergic agonist compound, an anti-inflammatory corticosteroid compound, an anticholinergics compound, and an anti-inflammatory.compound, and said containers optionally contain a pharmaceutical carrier.

Another preferred embodiment of the invention is a method for treating a patient suffering from a disease state capable of being modulated by inhibiting production of Factor Xa comprising administering to said patient a pharmaceutically effective amount of a compound of formula I.

Another preferred embodiment of the invention is a method of inhibiting factor Xa comprising 0 contacting a Factor Xa inhibitory amount of a compound of formula I with a composition containing Factor Xa.

Another preferred embodiment of the invention is a method of inhibiting the formation of thrombin comprising contacting Factor Xa inhibitory amount of a compound of formula I with a composition containing Factor Xa.

Another preferred embodiment of the invention is a method for treating a patient suffering from a physiological condition capable of being modulated by inhibiting production of Factor Xa comprising administering to said patient a pharmaceutically effective amount of a compound of formula I, wherein the physiological condition is selected from the group consisting of venous vasculature, arterial vasculature, abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy, percutaneous transluminal coronary angioplasty, transient ischemic attacks, stroke, intermittent claudication or bypass grafting of the coronary or peripheral arteries, vessel luminal narrowing, restenosis post coronary or venous angioplasty, maintenance of vascular access patency in long-term hemodialysis patients, pathologic thrombus formation occurring in the veins of the lower extremities following abdominal, knee and hip surgery, a risk of pulmonary thromboembolism, or disseminated systemic WO 01/81310 PCT/US01/13810 -16intravascular coagulopathy occurring in vascular systems during septic shock, certain viral infections and cancer.

Another further preferred embodiment of the invention is a pharmaceutical composition comprising a compound of formula I, and one or more of the following: a cardioprotective agent, a direct thrombin inhibitor, an anticoagulant, an antiplatelet agent or fibrinolytic agent, selected from: anti-coagulants such as warfarin, heparin or low molecular weight heparin; synthetic pentasaccharides; 0anti-platelet agents such as aspirin, piroxicam or ticlopidine; direct thrombin inhibitors (e.g.

Sboroarginine derivatives, hirudin or argatroban (Novastan)); fibrinogen receptor antagonists; statins Sfibrates; or fibrinolytic agents (thrombolytic agents) such as tissue plasminogen activator, anistreplase r- 10 (Eminase®), urokinase or streptokinase, Factor Xa inhibitors or Factor VIIa inhibitors; and a Spharmaceutically acceptable carrier.

Another further preferred embodiment of the invention is a pharmaceutical kit for treating or preventing a disease state capable of being modulated by inhibiting Factor Xa activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound of formula I and at least another of said containers contains one or more compounds selected from the group consisting of a cardioprotective agent, a direct thrombin inhibitor, an anticoagulant, anantiplatelet or fibrinolytic agent, and said containers optionally contain a pharmaceutical carrier.

A preferred compound aspect of the invention is the compound of formula I wherein is a single bond.

A preferred compound aspect of the invention is the compound of formula I wherein is a double bond.

A preferred compound aspect of the invention is the compound of formula I wherein X' and Xb are hydrogen and X" is selected from the group consisting of, R 4 RN-, (hydroxy)HN-, (alkoxy)HN-, R 6 R4RNCO-, R 4

RNSO

2

R

6 CO-, halo, cyano, nitro R 7 (0)C(CH 2 )q and

NR

10

NR'

1

H

2 N more preferably, X is H 2 N and R 1 0 is hydrogen, R or HO-.

A further preferred compound aspect of the invention is the compound of formula I wherein Z is a carbon atom; L- is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group; and R and R 2 are hydrogen.

A further preferred compound aspect of the invention is the compound of formula I wherein WO 01/81310 PCTIUS01/13810 -17-

C

Z is a nitrogen atom; is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group; is a single bond; and R' and R 2 are hydrogen.

A further preferred compound aspect of the invention is the compound of formula I wherein Z is a nitrogen atom; is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group; is a single bond; and R 1 is selected from the group consisting of hydrogen -CH 2

OR

12

-CH

2

SR

1 2

-CO

2

R

13

-C(O)R

13 and -CONR 3

R

13 A further preferred compound aspect of the invention is the compound of formula I wherein Z is a carbon atom; is a 6-membered azaheterocyclyl or a 6-membered azaheterocyclenyl group; and R is selected from the group consisting of hydrogen -CH2OR 1 2

-CH

2

SR'

2

-CO

2

R'

3

C(O)R

3 and-CONR 3

R'

3 A further preferred compound aspect of the invention is the compound of formula I wherein Z C is a carbon atom; is a 6-membered azaheterocyclenyl group; is a double bond; and R' and R 2 are hydrogen.

A preferred compound aspect of the invention is a compound of formula I wherein R 3 is aryl, heteroaryl or heterocyclyl; more preferably, R 3 is substituted phenyl.

A further preferred compound aspect of the invention is a compound of formula I wherein R 3 is optionally substituted (phenyl substituted aralkyl), optionally substituted (heteroaryl substituted aralkyl), optionally substituted (phenyl substituted heteroaralkyl) or optionally substituted (heteroaryl substituted heteroaralkyl), (wherein the term "optionally substituted" before the term in the parenthesis, denote that the phenyl, heteroaryl, aralkyl, or heteroaralkyl portions thereof could be further substituted as noted per their definitions).

A further preferred compound aspect of the invention is a compound of formula I wherein R 3 is optionally substituted (phenyl substituted aralkenyl), optionally substituted (heteroaryl substituted aralkenyl), optionally substituted (phenyl substituted heteroaralkenyl) or optionally substituted (heteroaryl substituted heteroaralkenyl), (wherein the term "optionally substituted" before the term in the parenthesis, denote that the phenyl, heteroaryl, aralkenyl or heteroaralkenyl portions thereof could be further substituted as noted per their definitions).

WO 01/81310 PCT/US01/13810 -18- A further preferred compound aspect of the invention is a compound of formula I wherein R 3 is optionally substituted (phenyl substituted aralkynl), optionally substituted (heteroaryl substituted aralkynl), optionally substituted (phenyl substituted heteroaralkynl) or optionally substituted (heteroaryl substituted heteroaralkynl), (wherein the term "optionally substituted" before the term in the parenthesis, denote that the phenyl, heteroaryl, aralkynl, heteroaralkynl portions thereof could be further substituted as noted per their definitions).

A more preferred compound aspect of the invention is a compound of formula I wherein R 3 is optionally substituted (phenyl substituted phenyl), optionally substituted (heteroaryl substituted phenyl), optionally substituted (phenyl substituted heteroaryl) or optionally substituted (heteroaryl substituted heteroaryl), (wherein the term "optionally substituted" before the term in the parenthesis, denote that the phenyl or heteroaryl portions thereof could be further substituted as noted per their definitions).

A preferred compound aspect of the invention is the compound of formula I wherein R' is hydrogen, -COR 1 2

-C(O)R

1 2

-CH

2 OR" or -CH 2 SR"; more preferred is hydrogen, -CO 2

R

1 2

CH

2 OR'" or -CH 2

SR

13 yet more preferred is hydrogen, -CO 2

R

1 2 or -CH 2

OR

13 and R 12 and R 13 are hydrogen or lower alkyl.

Another preferred compound aspect of the invention is the compound of formula I wherein X'

NR

o 1 is a H 2 N moiety and is an aryl group, a monocyclic heteroaryl group; more

NR

o 1 preferably, X is H 2 N and is in the meta position with respect to the position of attachment of the moiety to the moiety.

Another preferred compound aspect of the invention is the compound of formula I wherein O is aryl or a monocyclic heteroaryl group; and X 0 is selected from the group consisting of,

R

4 R (hydroxy)HN-, (alkoxy)HN-, R 6

R

4 RNCO-, R 4

RNSO

2

R

6 CO-, halo, cyano, nitro

NR

10 NRo 1

R

7

(O)C(CH

2 and H 2 N more preferably X is H 2

N

WO 01/81310 PCTfUSOI/13810 -19- Another preferred compound aspect of the invention is the compound of formula I wherein is a bicyclic azaheteroaryl group which includes a first proximal ring that is attached to the k l moiety and a ring distal to said first ring; )N s R 4

R

5 (hydroxy)HN-, or (alkoxy)HN-, and rC is in the alpha position to a nitrogen atom in said distal ring; for example, may be represented by a formula selected from the group consting of XcC a

N

N Aj jAr1 wherein Arl is the proximal ring portion of the bicyclic heteroaryl group.

Species according to the invention are selected from the following: 3-f{ 1-[4-(6-Oxo-l ,6-diliydropyridine-3-yl)-benzoyl]- 1,2,3,6-tetalhydropyridin-4 yl}benzamidine; 3- -Oxypyridin-2-yl)-benzoyl]- 1,2,3,6-tetrahydropyridin-4 yllbenzaxnidine; 3- I I -Oxypyridin-4-yl)-benzoyl}- 1 ,2,3,6-tetrahydropyridin-4-yl~benzamidine; 3- 1-[4-(6-Oxo- l,6-dihydropyridine-3-yl)-benzoyl]-piperidin-4-yI}benzamidine; 3- 1-Oxypyridin-4-yl)-benzoyl]-pipenidin-4-y }benzamidine; 3- l-Oxypyridin-2-yl)-benzoyl]-piperidin-4-yl} benzamidine; 1-(4-Pyridine-2-yI-benzoyl)- 1,2,3,6-tetrahydropyridin-4-yl]benzamidine; 3-4 l-(4-Pyridin-3 -yl-benzoyl)-l ,2,3 ,6-tetrahydropyridin-4-yllbenzainidine; 3-[l -(4-Pyridin-4-yl-benzoyl)-1 ,2,3,6-tetrahydropyridin-4-yl]benza9midine; 3- 1 -4-(5-Bromofuran-2-yI)-benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl) benzamnidine; 3- {I1 -[4-(5-Chlorothiophen-2-yl)-benzoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl~benzamidine; WO 01/81310 PCTJUSO1/13810 03- I -(4-Thiophen-2-yl-benzoyl)-1 ,2,3,6-tetahydropyridin4-yI} benzamidine; -[3-(5-Chlorothiophen-2-yl)-acryloyl)- 1 ,2,3,6-tetrahydropyridil-4-yi) benzaniidine; 3.41 {2.(2-Dimethylaminoethyl)methylamliflo]pyfllidifl4YI} benzoyl)- 1,2,3 ,6-tetrahydropyridin- 4-yI~benzamidine; {4-[2-.(2-Dimethylaminoethyl)-6-oxo- 1,6-dihydropyridin-3-y]bIzoyI}- 1,2,3,6tetrahydropyridin-4-yl)beflzamidfle; 3-[I -(4-Pyrimidin-2-ylbenzoyl)-1 ,2,3,6.-tetrahydropyridin4-yl]-benzamidlle; 3.4 l{(4Pyrzi-2-ylbenzoy)-1,2,3,6-terahydropyridin-4-yl]-beflzamidrne; I-(4'.-Sulfamoylbipheuyl4-carboflyl)-1 ,2,3,6-terahydropyridil--y]-belzamlidule; LO 3-[1 '-Sulfamoylbiphenyl4-carbonl)l>1,2,3,6.-tetrahydropyridin-4-yl]-beflzamidrne; 3- I -[-6Mtoyyiai--lbnol-,,36ttayrprdn4y]bnaiie 3-f 1,6 dihydropyridazin-3-y)belzoyl]- 1,2,3 ,6.-tetrahydropyridin-4-y]-belzamidile; 3- 1-[4-(2-Aminopyrimidin-5-y)belzoyl]- 1,2,3,6.-tetrahydropyridin-4-yi]-beflzamidlle; .44.(6..Methoxypyridin-3-y)belzoyl]- 1,2,3 ,6-tetrahydropyridin-4-y]-bllzamidifle; is I-(4-(Pyrimnidin-5-ylbenzoyl)- 1,2,3,6.-tetrahyciropyridin-4-yl]-belzamfidile; I -(4-Pyridin-2-ybenzoyl)-piperidin4-yl]benzamidile; 1 -(4-Pyrjdin-3.-ylbenzoyl).piperidil-4-y]benzamidile; 3-ti .(4.Pyridin-4.-ylbenzoyl)-piperidil-4-yIlbelzalidle; 3- 1 4.(6-Methoxypyridin-3-yl)benzoyl-piperdfl- 4 -yI} benzamidine; 3- (1 4(6-Methoxypyridazil-3-y1)beflzoyl]-piperidifl 4 -yl}benzamidine; 3-{11-[4-(6-Oxo- 1,6-dihydropyridazin-3-yl)beflzoyll-piperidifl-4-yl)beflzamidine; 1 .Axinoisoquinolin-7-yl)piperidime- 1-carbonyl]phenyl}- 1H-pyridin-2-one; 1-Amninoisoquinolin-7-yl)piperidifle-lI-carbonyl]- I'H-[2,3 ']bipyridinyl-6'--one; 1-Aminoisoquinolin-7-yl)piperidifl- -yl][2-fluor-4-(6.-methoxypyridin-3-y1)phenlY1mehaofe; 1-Am inoisoquinolin-7-yl)piperidin- 1.y1](2.-fluoro4-pyridin-3-y1phenyl)methaflone; 4'-114-( 1-Aminoisoquinolin-7-yl)piperidile- 1 .carbonyl]biphenyl-3-caboxylic acid amide; 1-Aminoisoquinolin-7-yl)piperdfl-1 .yl][5.-(6-methoxypyridin-3.yl)thiophefl2-yI]]methanone; 1 .Aminoisoquinolin-7y)piperidie--cabollV 3 fluorophenl}l) H-pyridin-2-one; 1-Aminoisoquinolin-7-yl)piperidine- 1-carbonyl]thiophen-2-yl} H-pyridin-2-one; 5- -Aminoisoquinolin-7-yl)-3 ,6-dfiydro-2H-pyridine- 1-carbonyl]phenyl} -1H-pyridin-2-one; 1 -Aminoisoquinolin-7-yl)-3,6-dihydro-2H-pyridin 1-y](4-pyridin-4-yIphenyI)methaflofe; 1-Aminoisoquinolin-7-y1)piperidifl- -yl] [4.-(6-methoxypyridin-3-y1)phelyl]methalofe; 1-Aminoisoquinolin-7-yI)piperidil- 1 -yl](4-pyridin-3-ylphenyl)methalofe; -Aminoisoquinolifl-7-y1)piperidifl 1-yl](6'-methoxy-12,3 5..{4.{4-(4-Amino- IH-pyrrolo[3 ,2-clpyridin-2-yl)piperidine- 1-carbonyliphenyl) H-pyridin-2-one; 5-[4-(4-Amino-l1H-pyrrolo[3 ,2-clpyridin-2-yl)piperidille- 1-carbonyl]-1 ']bipyridinyl-6'-one; 3.t1.(5-Phenylethy.-pyidine3-Obony)piperidin-4-yl]bel~aminife; WO 01/81310 PCT/US01/13810 -21- S3-[1-(5-Phenylethynyl-pyridine-3-carbonyl)- 1,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 3-[1-(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzamidine; and 3-[4-(5-Phenylethyl-pyridine-3-carbonyl)-piperazin-1-yl]-benzamidine.

It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.

Compounds of Formula I, wherein Z is a carbon atom, may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein.

NC X NC B(OH) 2

X

NC~y X X Br, I, OTr xa Xb X b n P protecting group X Xal' b M, R X IV, R

V

N

NCO Ar

X

8 b I 0 X8 xAr

NH

2

NH

2 N HN HN H0 2 C'a X Xbvm a b VI

IX,

xa b N NH2Ar 2 HN H0 2 C HN Xa b V X Xb Scheme 1 As illustrated in Scheme 1, an optionally substituted halobenzonitrile I is treated with an alkyl lithium in an aprotic solvent at low temperature followed by a trialkylborate to give compound U. A suitably activated coupling partner, such as protected 4-trifluoromethyl-sulfonyloxy-1,2,3,6tetrahydropyridine, prepared by published methods, and compound II are dissolved in a polar solvent such as acetonitrile and treated with an aqueous base such as sodium carbonate and a palladium catalyst such as palladium tetrakistriphenylphosphine at elevated temperature (80-100 OC) for about

P

=H

R=

WO 01/81310 PCT/US01113810 -22- 0 0.5 to 2 hours. The protected 1,2,3,6-tetrahydropyridinyl benzonitrile IT so obtained can be processed in a number of ways to obtain compounds of the current invention.

The nitrogen protecting group of compound m e. P) can be removed as appropriate to obtain compound IV; for example if the nitrogen protecting group is a BOC group, II is treated with a mineral acid such as HCI in ethyl acetate to obtain IV as the HC1 salt. This material can be reacted with an aryl carboxylic acid such as V in the presence of base and a suitable coupling reagent such as TBTU O to obtain Compound VI. Compound VI may then be converted to the benzamidine VII by treatment with Pinner conditions (HCl/ROH, wherein ROH can be methanol or ethanol) followed by O ammonolysis in protic solvents such as methanol at ambient temperature to 65 °C.

r> 10 Alternatively compound I wherein P is a BOC group can be treated under Pinner conditions Sfollowed by ammonolysis to yield compound IX directly. When P is an acid stable protecting group the protecting group may be removed in a separate step immediately following preparation of amidine VII using methods described above. In either case compound IX is treated with enough base to generate the free amine and aryl carboxylic acid V and a coupling reagent such as TBTU to give compounds VII.

Compounds of the invention such as XI can be obtained from the previously described intermediates IX by reduction of the double bond by any one of several reducing reagents such as palladium on carbon under a hydrogen gas atmosphere. Subsequent coupling with aryl carboxylic acid V as described above yields compounds XI. Alternatively compound VII may be reduced as a final step to give compound XI. It will be apparent to those skilled in the art that certain compounds of formula I can exhibit isomerism, for example geometrical isomerism, E or Z isomerism, and optical isomerism, R or S configurations. Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl moieties. Individual geometrical isomers and stereoisomers within formula I, and their mixtures, are within the scope of the invention.

Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.

In addition, as illustrated in Scheme 2, an optionally substituted-3-(4-bromophenyl)acrylic acid XII is converted to a suitably activated acid anhydride intermediate, and treated with sodium azide to give compound XIII. This material undergoes a thermally induced Curtius rearrangement, and base catalyzed cyclization to give isoquinolone XIV. Conversion of XIV to the chloride XV, and subsequent lithiation and treatment with trialkyl borate gives compound XVI. A suitably activated coupling partner, such as protected 4-trifluorosulfonyloxy-1,2,3,6-tetrahydropyridine XVII and compound XVI are subjected to standard Suzuki coupling conditions to give the key intermediate XVIII. Compound XVIII can either be deprotected to give-compound XIX, or can be subjected to ammonolysis conditions to give compound XXI. Compound XIX can be reacted with an appropriate WO 01/81310 PCT/US01/13810 -23carboxylic acid derivative, pre-activated with a suitable coupling agent such as TBTU, to give compound XX. Ammonolysis of XX gives one potential final product compound XXIV. Compound XXIV can be carefully reduced with selective reduction conditions, such as H 2 palladium on carbon, to give final product XXV. Compound XXI (previously obtained from XVIII) can be deprotected to give compound XXII. Compound XXII can either be reduced as described above to give compound XXIII; or alternatively, coupled with the appropriate carboxylic acid to give final product XXTV.

Compound XXIII can be coupled with the appropriate carboxylic acid (again, as previously described) to give final product XXV.

rN'H Xb a X X8 r b X Br OH OrN HO OH X=Br, l,OTf p P protecting group X -P

XVII

txv NH2 NCI CI I -Xb Xb Xb b X X a Xa NXXIV N N N k O R3 Aryl, heteroaryl, biaryl heteroblaryl, biheteroaryl NH

N

1 bb a a X N xxv xXII xxn X X I O R 3 j N XXII NN Scheme 2 Compounds of Formula I, wherein Z is a nitrogen atom, can be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, or by methods according to this invention herein.

WO 01/81310 PCT/US01/13810 -24- F a N b N c

N

X

a N N N X XVX N CN

CN

XXVI XXVII XXVIII

XXIX

Xb ring system substituent; R 3 aryl, heteroaryl, alkyl, cycloalkyl, heterocyclyl.

Reagents: a) piperazine, DMSO, 100 oC; b) RCO 2 H, O-(7-Azabenzotriazol-1-yl)-NN,N,Ntetramethyluronium hexafluorophosphate (HATU), Diisopropylethylamine (DIPEA), DMF; c) HCI(g), MeOH then NH 3 MeOH.

Scheme 3 As illustrated in Scheme 3 above, an appropriately substituted fluorobenzonitrile compound of formula XXVI can be treated with an optionally substituted piperazine compound, in dimethylsulphoxide (20 ml) and heated at 100 °C for 48 hours under an atmosphere of nitrogen, to afford a piperazine intermediate compound of formula XXVII. The piperazine intermediate compound of formula XXVII can then be isolated using known purification techniques, for example, flash chromatography.

The isolated piperazine intermediate compound of formula XXVII is then reacted with a suitable carboxylic acid compound of formula R 3 COOH in anhydrous dimethylformamide, in the presence of HATU and diisopropylethylamine, at ambient temperature for 18 hours, to afford the desired amide intermediate compound of formula XXVIII.

A methanolic solution of an amide intermediate compound of formula XXVIII is cooled to 0 °C and saturated with hydrogen chloride gas. The reaction vessel is sealed and allowed to stand at 0 °C for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (20 ml) and cooled to0 The solution is saturated with ammonia gas and the vessel' sealed before being allowed to stand at 0 °C for 48 hours. The reaction mixture is then concentrated to dryness under vacuum and the desired compound XXIX is isolated by known purification techniques.

The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.

Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in WO 01/81310 PCT[US01/13810 0 0 pharmaceutical doses of the salts, so that the beneficial inhibitory effects on Factor Xa inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.

Pharmaceutically acceptable salts within the scope of the invention are those derived from the '1 following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-bydroxynaphthoates, gentisates, mesylates, isethionates and di-ptoluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on Factor Xa inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, WO 01/81310 PCT/US01/13810 -26ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.

Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.

Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.

The base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.

Pharmaceutically acceptable salts also include quaternary lower alkyl ammonium salts. The quaternary salts are prepared by the exhaustive alkylation of basic nitrogen atoms in compounds, including nonaromatic and aromatic basic nitrogen atoms, according to the invention, alkylating the non-bonded pair of electrons of the nitrogen moieties with an alkylating agent such as methylhalide, particularly methyl iodide, or dimethyl sulfate. Quarterarization results in the nitrogen moiety becoming positively charged and having a negative counter ion associated therewith.

As will be self-evident to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are most likely to be formed by compounds of this invention having a nitrogen-containing heteroaryl group and/or wherein the compounds contain an amino group as a substituent. Preferable acid addition salts of the compounds of the invention are those wherein there is not an acid labile group.

As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.

The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents, or by methods according to this invention.

WO 01/81310 PCTIUS01/13810 -27- The present invention is further exemplified but not limited by the following illustrative examples which illustrate the preparation of the compounds according to the invention.

In the nuclear magnetic resonance spectra (NMR) the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significance: s=singlet; d~doublet; t--triplet; m=multiplet, dd=doublet of doublets; ddcfrdoublet of doublets of doublets; dt=:doublet of triplets, b--broad.

EXAMPLE 1 3-f{ 1 -I4-(6-Oxo-1,6-dihydropyridine-3-yl)-benzoyl]-l ,2,3,6-tetrahydropyridin-4 yl}benzamidine 0 trifluoroacetate.

A. 3-Cyanophenyl boronic acid 3-Bromobenzonitrile (3.6 g; 20 mmrol) in anhydrous TIF (100 ml) is treated with triisopropyl borate (13 ml, 56 mmol) followed by 1.6 M butyllithium in hexane (14 ml, 22 mmol) over 15 min. at -78 *C.

The reaction is stirred at -78 TC for 45 min then warmed to room temperature over 60 min. The reaction mixture is poured into 40 ml 2 N HC1 and the precipitated solid is collected The filter cake is washed with water (3X) and methylene chloride (3X) to yield 3-cyanophenyl boronic acid (2.3 g, 15.6 minol). 'H NMR (CDCl 3 300 MIHz) 5 8.4 (br, 211), 8.13 111), 8.07 111), 7.85 (di, IH), 7.55 (t, 11H). EI MS W~ 147.

.0 B. 3-(1 ,2,3 ,6-Tetrahydropyridine-4-yl)benzonitrile 3-Cyanophenyl boronic acid (3.0 g, 20.4 mmol) and 4-(trifluoromethaneulfonyloxy)-3,6-dihydro-2Hpyridine. I1-carboxylic acid tert-butyl ester (7.0 g, 2 1.1 mmol) are dissolved in acetonitrile (100 ml) and 0.4 M aqueous sodium carbonate (100 ml). The solution is degassed and treated with palladium tetrakistriphenylphosphine (1.2 g, 1.04 rumol) at 90 IC for I hour. The reaction is cooled, filtered and the filtrate is concentrated to an oil. The oil is extracted with methylene chloride (3X) and the solvent is removed under vacuum. The residue is chromatographed (15% ethyl acetate/hexane) to give the title compound as a white solid (6.0 g, 21.1 inmol). This material is treated with methylene chloride (1 O0ml) and 40% ITAmethylene chloride (I Q0mi) at ambient temperature for 2 h. The solvents are removed under vacuum and the residue is chroniatographed (N11 4 01{IMeOICH 2 Cl 2 1:5:94) to give title compound as a brown solid contaminated with inorganic salts (4.6 JH NMR (CDCl 3 3 00 MHz) 57.87 111), 7.80 (di, IM), 7.70 (di, 1H), 7.58 1117, 6,28 (in, 111), 3.90 (in, 211), 3.49 2H1), 2.83 (in, 2H1). El MS Wi 184.

C. 3- 1-4-(6-Methoxypyridin-3-yl)-benzoyl- 1 ,2,3,6-tetrahydropyridin-4 yllbenzonitrile 6-Methoxypyridin-3-ylbenzoic acid (0.7 g, 2.6 inmol) is treated with triethyl amine (0.7 ml, 5 mmol) and TBTU (0.95 g, 3.0 mmol) in DNvi (5 ml). 3-(1 ,2,3,6-Tetrahydropyridin-4-yl)benzonitrile (0.9 g), WO 01/81310 PCT[US01/13810 -28prepared as above, is added to this suspension and the reaction mixture is heated to 35 'C with stirring for 1.5 h. Solvent is removed, the residue is dissolved in ethyl acetate, and the solution is washed with IN HCI (2 X 5 ml). The precipitated solid, 3-{1-[4-(6-methoxypyridin-3-yl)-benzoyl]-1,2,3,6tetrahydropyridin-4 yl) benzonitrile, is collected (0.60 a second crop 15 g) is obtained by saturating the organic layer with HCl. 'HNMR (DMSO) 8 8.53 lIH), 8.10 111), 7.90 111), 7.75 (in, 4H), 4.30 (mn, 3H1), 6.95 111), 6.3 (br, 4.2 (br, 214), 3.87 3H1), 3.5 (br, 211), 2.6 (br, 2M). Ion spray MS Mv'+1: 396.

D. 3- 1-[4-(6-Oxo-1 ,6-dihydropyridin-3-y)-benzoyll-1 ,2,3 ,6-tetrahydropyridin-4 yl}benzonitrile The combined solids from Part C (0.75 g, 1.7 minol) are treated with pyridine hydrochloride (2.0 g, 17 inmol) and heated to 160 *C for 15 min. The reaction mixture is cooled and treated with ice water, the resulting white solid is collected and washed repeatedly with water and ethyl acetate. Vacuum drying yields the title compound as an off white solid (0.55 g, 1.4 inmol). Ion spray MS Mt+1: 382.

E 3-f 1,6-dihydropyridine-3-yl)-benzoyll-1I,2,3,6-tetrahydropyridin-4 yllbenzamidine trifluoroacetate.

3- I-[4-(6-Oxo- 1,6-dihydropyridin-3-yl)-benzoyl]- 1,2,3,6-tetrahydropyridin-4 yI~benzonitrile from repeat runs (1.5 g, 3.9 mmol) is dissolved in methanol (200 ml), cooled in an ice bath and saturated with HCI gas. The reaction vessel is sealed and the solution is stirred overnight at ambient temperature.

The solvents are removed under vacuum and the residue is re-dissolved in methanol. The solution is saturated with ammonia; the reaction vessel is sealed and stirred at ambient temperature overnight. The volatiles are removed and the residue is treated with 0.1% aqueous TFAlacetonitrile/methanol. The precipitated solid is removed and the filtrate is subjected to reverse phase HPLC purification.

Lyophilization of the fractions containing product yield the title compound as an amorphous solid (0.35 g, 0.68 nimol). 'H NMR (DMSO) 8 11.9 (br, 111), 9.30.(s, 211M, 9.12 2H1), 7.8 (mn, 411, 7.7 (in, 4H), 7.47 211), 6.42 111), 6.3 (br, 111, 4.2 (br, 211, 3.7 (br, 211), 2.6 (br, 211). Ion spray MS M+l: 399.

EXAMPLE 2 1-Oxypyridin-2-yl)-b2enzoyl- 1,2,3,6-tetrahydropyr'di- lbeamdntrfooctte 1,2,3,6-Tetrahydropyridin-4-yl)benzamidine dihydrochloride (0.02 8 g, 0.10 inmol) is added to a solution of 4-(1-oxypyridin-2-yl)-benzoic acid (0.027 g, 0.10 minol), triethyl amine (0.045 ml, 0.33 mmol) and TBTtJ (0.035 g, 0.11 mmiol) in DMF (1 ml). The reaction mixture is stirred at ambient temperature for 2 h and the solvent is removed with a stream of nitrogen. The residue is purified by reverse phase IiPLO to give the title compound as an amorphous solid (0.023 g, 0.037 mmol). 1H1 WO 01/81310 PCTfUS01/13816 -29- 0NmR (DMSO) 5 9.30 2ff), 9.0 211), 8.36 (in, 1Hi), 7.93 (di, 21-1), 7.8 (in, 211), 7,68 (mn, 2H1), 7.6 (mn, 211), 7.42 (in, 6.3 (br, 111, 4.2 (br, 211'), 3.7 (br, 211), 2.6 (br, 2H). Ion spray MS M+1: 399.

EXAMP2LE 3 3- 1 -Oxypyridin-4-yl)-benzoyl]- 1,2,3,6-tetrahydropyridin-4-yl} benzamnidine trifluoroacetate.

The title compound (0.013 g, 0.021 minol) is prepared as described in Example 2 using 4-(1-Oxypyridin-4-yl)-benzoic acid (0.027 g, 0.10 inmol). 'H NMvR (DMSO) 8 9.32 2H1), 8.98 211), 8.39 ri (di, 211), 7.5-7.9 (in, 1011), 6.3 (br, 1M1, 4.2 (br, 211), 3.7 (br, 211), 2.6 (br, 211). Ion spray MS Mi+1: Ni 399.

ri EX-AMLE 4 3- (1-[4-(6-Oxo-1I,6-dihydropyridin-3-yl)-benzoyll-piperidin-4-yl }benzamidine trifluoroacetate.

A. 4-(3-Cyanophenyl)-3,6-diliydro-2H-pyridin-1-carboxylic acid tert-butyl ester 3-Cyanophenyl boronic acid (1.8 g, 12.2 inmol) and 4-(frifluoromethanesulfonyloxy)-3,6-dihydro-2Hpyridine-lI-carboxylic acid tert-butyl ester (5.0g, 15.2 minol;) are dissolved in acetonitrile (60 ml) and 0.4 M aqueous sodium carbonate (60 ml). The solution is degassed and treated with palladium tetrakistriphenyl phosphine (0.8 1ig, 0.7mmol) at 90 'C for 1 hour. The reaction is cooled, filtered warmed and the filtrate is concentrated to an oil. The oil is extracted with methylene chloride (3X) and the solvent is removed under vacuum. The residue is chromatographed (15% ethyl acetate/hexane) to give the title compound as a white solid (2.7 g, 9.5 mmol). 11H NNM (CDC1 3 300 MfHz) 8 7.63 111, 7.55 (mn, 211), 7.44 111), 6. 10 (br, 111), 4.09 (mn, 211), 3.63 211), 2.50 (br, 211). El MIS 285.

B. 3-(1I,2,3,6-Tetrahydropyridin-4-yl)benzamidine dihydrochioride.

4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine--carboxylic acid tert-butyl ester (3.4 g, 12.0 nimol) is dissolved in anhydrous methanol (300 ml), cooled in an ice bath and saturated with a stream of H1 gas. The reaction vessel is sealed and the solution is stirred overnight at ambient temperature. The solvent is removed and the residue is re-dissolved in methanol (300 ml). The resulting solution is saturated with ammonia gas, the vessel is sealed and stfirred overnight at room temperature. The solvent is removed in vacuo and the residue is dissolved in dilute aqueous HCl and purified by reverse phase HIPLC (acetonitile/H20, 2:98). Fractions containing product are lyophilized to yield the title compound as a white solid (1.7 g, 6.2 mmol). 1 H NMR (DM50) 8 9.48 211), 9.38 211), 9.15 (s, 211), 7.90 111'), 7.80 111), 7.73 (di, 111), 7.58 111), 6.39 111), 3.76 (br, 211, 3.3 (br, 211, 1.9 4H). El MS M 4 201.

C. 3-Piperidin-4-ylbenzamnidine dihydrochioride.

WO 01/81310 PCTfUS01/13810 3-(1,2,3,6-.Tetrahydropyridin-4-yI)benzamidine dihydrochioride (1.0 g, 5.0 mmol) is dissolved in methanol (50 ml) treated with 5% Pd on carbon and stirred overnight under an atmosphere of hydrogen gas. The reaction mixture is filtered; the filtrate is concentrated to give 3-piperidin-4ylbenzamidine dihydrochioride as a white foam (1.30 g, 4.7 inmol). 'H NMR (DM80) 5 9.40 2H1), 9.2 (br, 411), 7.67 (br, 211), 7.56 (br, 211), 3.4 (br, 211), 3.0 (in, 3M1, 2.7 (br, 411). Ion spray MS M+1: 204.

D. 3- {1-[4-(6-Oxo-1 ,6-dihydropyridine-3-y1)-benzoyll-r'iperidin-4-y}belzawfidine trifluoroacetate.

1-[4-(6-Oxo-1,6-dihydropyridin-3-yI)-benzoic acid (0.86 g, 4.0 inmol) is suspended in DMF (8 ml), treated with TBTU (1.4 g, 4.4 mmol), iriethylamine, (1.7 ml, 12 inmol) and 3-piperidinylbenzamidine dihydrochioride (1.1 g, 4.0 inmol). The reaction mixture is heated to 3 5 TC for 2 h. The solvent is removed and the residue is subjected to reverse phase HPLC purification to yield the title compound as an amorphous solid (1.3 g, 2.5 minol). 111NMR (DMSO) 5 11.8 (br, 111), 9.30 211), 9.12 211, 7.9-7.4(m, 1011), 6.47 111), 4.6 (br, 111), 3.7 (br, 111), 3.2 (br, 2.9 (in, 211), 1.75 (mn, 411). Ion spray MS W+1: 40 1.

EXAMPLE 3- 1-Oxypyridin-4-yl)-bnzoyll-piperidin-4-yl} benzamidine ditrifluoroacetate 3-Piperidin-4-ylbenzainidine dihydfochloride (0.028 g, 0. 10 minol) is added to a solution of 4-(1 oxypyridin-4-yl)benzoic acid (0.027 g, 0.10 mmiol), triethyl amine (0.045 ml, 0.33 mmol) and TBTU (0.03 5 g, 0. 11 inmol) in DMF (I ml). The reaction mixture is stirred at ambient temperature for 2 h and the solvent is removed with a stream of nitrogen. The residue is purified by reverse phase HPLC to give the title compound as an amorphous solid (0.0 12 g, 0.0 19 inmol). 1 H NMR (DMSO) 589.27 (s, 2H1), 8.95 211), 8.27 211), 7.88-7.50 (in, 1011), 4.6 (br, 111), 3.7 (br, 111), 3.2 (br, 1IM, 2.9 (in, 2H1), 1.75 (mn, 411). Ion spray MS M+1: 401.

EXAMPLE 6 3- 1-Oxypyridin-2-yl)-benzoyl]-piperidin-4-yllbenzamidifle ditrifluoroacetate The title compound (0.028 g, 0.045 inmol) is prepared as described in example 5 using 1oxypyridin-2-yl)-benzoic acid (0.027 g, 0.10 minol). '11 NMR (DMSO) 859.27 211, 8.95 211), 8.35 (in, 111, 7.88 211, 7.70-7.40 (in, 9H1), 4.6 (br, 111), 3.7 (br, IM1, 3.2 (br, 1IM, 2.9 (in, 2H1), 1.75 (in, 411). Ion spray MS M+1: 401.

EXAMPLE 7 3-f 1-(4-Pyridin-2-yl-benzoyl)- 1,2,3 ,6-tet-ahydropyridin-4-yllbenzamidine trifluoroacetate.

4-Pyridin-2-yl-benzoic acid (0.0 12 g, 0.05 iniol) is treated in succession with a freshly prepared solution of 0.25 M TBTU in DMF (0.20 ml, 0. 10 minol), triethyl amine (0.0 15 ml, 0. 10 inmol), and a WO 01/81310 PCTfUSOI/13810 -31slurry of 3-(l,2,3,6-tetrahydropyridin-4-yI)benzamidine dihydrochioride (0.011 g, 0.04 mmol) and triethylamine (0.015 ml, 0.10 mmol) in DMF (0.2 ml). The reaction mixture is stirred at 35 0 C for 1.5 h and the solvent is removed with a stream of nitrogen. The residue is purified by reverse phase HPLC to give the title compound as an amorphous solid (0.007 g, 0.012 nmol). 1 H NMR (DMSO) 8 9.30 (s, 21), 8.90 2H), 8.70 111), 8.13 21), 8.02 111), 7.95-7.53 91), 7.42 11), 6.3 (br, 111), 4.2 (br, 21), 3.7 (br, 21), 2.6 (br, 211). Ion spray MS 383.

In a like manner, by the method described in EXAMPLE 7, the compounds of EXAMPLES 8 to 23 are prepared: 0 EXAMPLE 8 3-1-(4-Pyridin-3-yl-benzoyl) 1,2,3 ,6-tetrahydropyridin-4-yl]benzamidine ditrifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzanidine dihydrochioride and 4-pyridin-3-yl-benzoic acid. 'H NMR (DMSO) 8 9.30 2H), 8.90 311), 8.52 11), 8.18 (d, 111), 7.85-7.52 91), 6.3 (br, 1H), 4.2 (br, 21), 3.7 (br, 211), 2.6 (br, 211). Ion spray MS M+l: 383.

EXAMPLE 9 3-[1-(4-Pyridin-4-yl-benzoyl)-1,2,3,6-tetrahydropyridin-4-yllbenzamidine ditrifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetahydropyridin-4-yl)benzamidine dihydrochioride !0 and 4-pyridin-4-yl-benzoic acid. 'H NMR (DMSO) 8 9.30 211), 8.90 21), 8.70 21), 7.95-7.53 1111), 6.3 (br, 1 4.2 (br, 211), 3.7 (br, 21), 2.6 (br, 211). Ion spray MS Mi+1: 383.

EXAMPLE 3- {1-[4-(5-Bromofuran-2-y)-benzoy- 1,2,3,6-tetrahydropyridin-4-yI I benzamidine trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4-(5-broiofuran-2-yl)-benzoic acid. 'H NMR (DMSO) 8 9.30 211), 8.90 21), 7.85-7.48 (m, 81), 7.13 11), 6.74 6.3 (br, 1H), 4.2 (br, 21), 3.7 (br, 21), 2.6 (br, 211). Ion spray MS M+1: 450,452.

EXAMPLE 11 3-{1-[4-(5-Chlorothiophen-2-yl-benzoyll- 1,2,3,6-tetrahydropyridin-4-yl}benzamidine trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4-(5-chlorothiophen-2-yI)-benzoic acid. 'H NMR (DMSO) 8 9.30 21), 8.98 21), 7.82-7.48 911), 7.22 111), 6.3 (br, 1I), 4.2 (br, 21), 3.7 (br, 21), 2.6 (br, 21). Ion spray MS M+1: 422,423.

WO 01/81310 PCT[US01/13810 -32- EXAMPLE 12 3- (11-(4-Thiophen-2-yl-benzoyl)- 1,2,3,6-tetrahydropyridin-4-yl} benzamidine trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4-thiophen-2-yl-benzoic acid. 'H1 NMR (DMSO) 859.30 2H), 8.98 211), 7.82-7.60 (in, 811), 7.48 211), 7.20 111), 6.3 (br, 111), 4.2 (br, 2117, 3.7 (br, 211', 2.6 (br, 21M. Ion spray MS I+: 388.

EXAMPLE 13 3-1 l-[3-(5-Chlorothiophen-2-yl)-acryloyl)-1 ,2,3 ,6-tetrahydropyridin-4-yl}benzamidine trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 3-(5-chlorothiophen-2-yl)-acrylic acid. '1H NMR (DMS0) 8 9.30 211), 9.0 211), 7.87-7.54 (mn, 51H), 7.37 IM,~ 7.13 111), 6.95 (in, 111), 6.37 (br, 111), 4.38 (br, 111), 4.25 (br, 111), 3.86 (br, III), 3.76 (br, 111), 2.6 (br, 211'. Ion spray MS M+1: 372, 374.

EXAMPLE 14 {2-[(2-Dimethylaminoethyl)nethylaminolpyriinidin-4-yl}benzoyl)- 1,2,3,6-tetrahydrop rdin- 4-yl }benzamidine ditrffluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4- {2-[(2-Dimnethylaminoethyl)methylamino]pyrimidin-4-yl)benzoic acid. 1H NMR (DMSO) 9.3 0 (br, 311), 9.02 211), 8.49 1ff), 8.24 (cd, 211), 8.05 1117, 7.90-7.70 (in, 3H1), 7.56 (di, 211), 7.30 (di, 111), 6.3 (br, 111), 4.2 (br, 211), 4.05 (mn, 211, 3.7 (br, 2117, 3.38 (in, 411), 3.20 311), 2.90 (s, 611), 2.6 (br, 211). Ion spray MS MW+1: 484.

EXAMPLE {4-12-(2-Dimethylaminoethyl)-6-oxo- 1,6-dihydropyridin-3-yllbenzoyl}- 1,2,3,6teurahydropyridin-4-YI)benzamidine ditrifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4-[2-(2-dimethylaminoethyl)-6-oxo- I ,6-dihydropyridin-3-yl]benzoic acid. 'H1 NNM (DMSO) 8 9.49 (br, 111, 9.30 (br, 211), 9.0 211), 8.20 (di, 111), 7.90 (dd, 111, 7.80-7.50 (mn, 811), 6.55 (ci, 111), 6.3 (br, 111), 4.3 0 (mn, 211), 4.2 (br, 211, 3.7 (br, 211), 2.86 61-1), 2.6 (br, 2H1). Ion spray MS M+l 470.

EXAMPLE 16 3-171-(4-Pyrimidin-2-ylbenzoyl)- 1,2,3,6-tet-ahydropyridin-4-yl]-benzamidine ditrifluoroacetate.

WO 01/81310 PCT[US01/13810 -33- The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzainidine dihydrochioride and 4-(pyrim idin-2-yl)benzoic acid. 1H NMvR (DMS0) 5 9.3 0 2H), 8.95 (in, 4H1), 8.49 2H), 7.87-7.53 (mn, 6H1), 7.50 111), 6.3 (br, 111), 4.2 (br, 211), 3.7 (br, 2H), 2.6 (br, 211). Ion spray MS Mi+1: 384.

EXAMPLE 17 I-(4-Pyrazin-2-ylbenzoyl)71,2,3,6-tetrahyrpyridin-4-yfl-benzamidine ditrifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzainidine dihydrochioride and 4-(pyrazin-2-yl)benzoic acid. 1H1 NMR (DMSO) 8 9.30 311), 8.98 211), 8.75 1H1), 8.62 (d, 111), 8.24 2H1), 8.49 211), 7.82-7.55 (in, 411), 6.3 (br, I 4.2 (br, 211), 3.7 (br, 211), 2.6 (br, 2H1).

Ion spray MS 384.

EXAMPLE 18 I-(4'-Sulfamoylbiphenyl-4-carbonyl)- 1,2,3,6-tetraliydropyridin-4-yl]-benzamidine trifluoroacetate.

The title compound is prepared from 3-(1,2,,6-tetrahydropyridin-4-yl)benzamidine diliydrochloride and 4'-sulfanioylbiphenyl-4-carbonic acid. 1H NM'R (DMSO) 5 9.30 2H1), 8.88 211), 7.87-7.52 (mn, 1211), 7.40 211, 6.3 (br, 1I17), 4.2 (br, 211), 3.7 (br, 211), 2.6 (br, 2H1). Ion spray MS M+1: 46 1.

EXAMPLE 19 !0 1 '-Sulfamoylbipheny-4carbonyl)- 1,2,3 ,6-tetrahydropyridin-4-yll-benzaniidine trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamnidine dihydrochioride and 3 '-sulfamoylbiphenyl-4-carbonic acid. 'H NMR (DMSO) 89.30 2H1), 8.88 21D), 8.12 111), 7.93-7.52 (mn, 1111), 7.40 211), 6.3 (br, 111), 4.2 (br, 211, 3.7 (br, 211), 2.6 (br, 211). Ion spray MS fvf+1: 461.

EXAMPLE 3- {11-[4-(6-Methoxypyridazin-3-yl)benzoyl]- 1,2,3,6-tetrahydropyridin-4-yll-benzamidine trifluoroacetate.

The title compound is prepared from 3-(1 ,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4-(6-methoxypyridazin-3-yl)benzoic acid. 1H NMR (DMSO) 8 9.30 211), 8.90 2H1), 8.22 (di, 111), 8.17 211, 7.85-7.52 (mn, 611), 7.32 (di, 111), 6.3 (br, 111), 4.2 (br, 211), 4.07 3M17, 3.7 (br, 211), 2.6 (br, 2H). Ion spray MS M+1: 414.

EXAMPLE 21 3-1{1 -I4-(6-Oxo- 1,6 dihydropyridazin-3-yl)benzoyll- 1,2,3,6-tetrahydropyridin-4-yll-benzanhidine trifluoroacetate.

WO 01/81310 PCT[US01/13810 -34- The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzalnidine dihydrochloride and 4-(6-oxo-I,6-dihydropyridazin-3-yl)benzoic acid. 'HNMR (DMSO) 8 13.3 (br, 111), 9.30 2H1), 8.88 2H1), 8.04 7.95-7.52 (in, 8ff), 7.00 111), 6.3 (br, 1H1), 4.2 (br, 2H), 3.7 (br, 2M1, 2.6 (br, 2M1. Ion spray MS M+l: 400.

EXAM4PLE 22 3-f{ 1-[4-(2-Aminopyrimidin-5-yl)benzoyll- 1,2,3,6-tetrahydropyridin-4.yl]-benzamidine trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamfidifle dihydrochioride 10 and 4-(2-aminopyrimidin-5-yl)benzoic acid. 1 H NMR (DMS0) 8 9.3 0 2H7), 8.90 2H1), 8.60 (s, 2H1), 7.85-7.50 (in, 81-1), 6.85 (br, 2H1), 6.3 (br, 1H1), 4.2 (br, 211), 3.7 (br, 211), 2.6 (br, 211). Ion spray MS M+1: 399.

EXAMPLE 23 3- -[4-(6-Methoxypyridin-3-yl)benzoyl]- 1,2,3,6-tetrahydropyridi-4-yl]-benzanidifle trifluoroacetate.

The title compound is prepared from 3-(1,2,3,6-tetrahydropyridin-4-yl)benzamidine dihydrochioride and 4-(6..methoxypyri din-3-yl)benzoic acid. 'H NMR (DM50) 8 9.30 2H1), 8.90 211), 8.53 (d, 1H1), 8.05 (dd, 1H1), 7.82-7.52 (in, 8M1, 6.90 6.3 (br, 111, 4.2 (br, 3.88 3H1), 3.7 (br, 2M1, 2.6 (br, 2H1). Ion spray MS, M+1: 413.

EXAMPLE 24 3-Fl -(4-(Pyrimidin-5-ylbenzoyl)- 1,2,3,6-tet-ahydropyridin-4-yl]-benzamidifle trifluoroacetate.

acid (0.0 12 g, 0.08 minol) is treated with triethyl amine (0.030 ml, 0.22 miunol), TBTU (0,018 g, minol), and 3-(1,2,3,6-tetrahydropyridin-4-yl)benzaxnidine dihydrochioride (0.022 g, 0.08 minol) in DMFf as described in EXAMPLE 5. Standard purification yields the title compound' 8 9.30 2M1, 9.21 111), 9.18 211), 8.98 211), 7.90-7.53 (mn, 811), 6.3 (br, 111), 4.2 (br, 211'), 3.7 (br, 2.6 (br, 21-1). Ion spray MS 3 84.

EXAMPLE 3-fl .(4-Pyridin-2-ylbenzoyl)-piperidin-4-y]benzanlidile ditrifluoroacetate A. 3-C 1,2,3 ,6-Tet-ahydropyridin-4-yI)benzamidine ditrifluoroacetate.

4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-caboxylic acid tert-butyl ester (2.2 g, mmiol) is treated as described in EXAMPLE 4, Part B. Reverse phase HPLC purification (5 to 40% acetonitrile in 0.1 aqueous trifluoroacetic acid) yields the title compound as a white solid (1.4 g, 2.6 inmol). El MS M+: 201 WO 01/81310 PCTfUS01/13810 B. 3-Piperidin-4-ylbenzaniidine ditrifluoroacetate.

3-(1 ,2,3,6-Tetrahydropyridin-4-yl)benzamidine ditrifluoroacetate (0.44 g, 1.02 mmol) is treated as described in EXAMPLE 2, Part D to give the title compound as a white solid. (0.44 g, 1.02 mmol). 1H NUR (DMSO) 8 9.30 211), 9.02 211), 8.80 (br, IM1, 8.60 (br, 111), 7.70-7.53 (in, 4H), 3.37 (br, 1ff, 2.95 (in, 411, 1.90 (mn, 411'). Ion spray MS l: 204.

C. 3-[1-(4-Pyridin-2-ylbenzoyl)-piperidin-4-yljbenzamidine ditrifluoroacetate 4-Pyridin-2-yl-benzoic acid (0.0 12 g, 0.05 minol) is treated in succession with TBTU (0.0 17g, 0..05 0 nimol), DMFf (0.4 ml), triethylainine (0.030 ml, 0.20 minol) and 3-piperidin-4-ylbenzaniidine ditrifluoroacetate (0.022 g, 0.05 mmol). The reaction mixture is stirred at 35 0 C for 1 h and the solvent is removed with a stream of nitrogen. The residue is purified by reverse phase H1PLC to give the title compound as an amorphous white solid (0.007 g, 0.011 inmol). IHNMR (DMS0) 8 9.25 21-1), 8.87 211), 8.68 IM1, 8.15 (di, 211), 8.00 (di, IM1, 7.90-7.50 (in, 7Bf), 7.35 (in, 111), 4.6 (br, 111), 3.7 (br, 111), 3.2 (br, I1H), 2.9 (in, 2M1, 1. 75 (in, 411). Ion spray MIS M+ 1: 385.

In a like manner, by the method described in EXAMPLE 25, the compounds of EXAMVPLES 26 to are prepared: EXAMPLE 26 1-(4-Pyridin-3-ylbenzoyl)-piperidin-4-yllbenzamidine ditrifluoroacetate The title compound is prepared from 3-piperidin-4-ylbenzamidine ditrifluoroacetate and 4-pyridine-3yl-benzoic acid. 1H NNvf (DMSO) 5 9.24 211), 8.90 (in, 311, 8.60 (di, 11-1), 8.20 (dd, 111), 7.80-7.48 (in, 911), 4.6 (br, 1ff), 3.7 (br, 111); 3.2 (br, 111), 2.9 (in, 211, 1.75 (in, 41-1). Ion spray MS M+1: 385.

EXAMPLE 27 341 -(4-Pyridin-4-ylbenzoyl)-piperidin-4-yl]benzamidine ditrifluoroacetate The title compound is prepared from 3-piperidin4-ylbenzainidine difrifluoroacetate and 4-pyridine-4yl-benzoic acid. 'H NM (DMSO) 5 9.24 211), 8.90 211), 8.70 (di, 2H1), 7.90-7.52 (in, 1011), 4.6 (br, 111), 3.7 (br, 111), 3.2 (br, 111), 2.9 (in, 2M1, 1.75 (in, 411. Ion spray MS M+l: 385.

EXAMPLE 28 3- -[4-(6-Methoxypyridin-3-yl)benzoyl-piperidil-4-yl}benzamfidine trifluoroacetate The title compound is prepared from 3-piperidin-4-ylbenzamidine ditrifluoroacetate and 4-(6methoxypyridin-3-yl)benzoic acid. NMR (DM50) 5 9.27 21-1), 9.02 211), 8.51 (di, 11H), 8.03 WO 01/81310 PCTIUS01/13810 -36- (dcl, IM1, 7.75-7.50 (in, 811, 6.88 111), 4.6 (br, 1M1, 3.87 311), 3.7 (br, 111), 3.2 (br, 1M1, 2.9 (mn, 21H), 1.75 (mn, 411). Ion spray MS M+l: 415.

EXAMPLE 29 1 5 3- 14-(6-Methoxypyridazin-3-yl)benzoyll-piperidin4-yl~benzamidile trifluoroacetate The title compound is prepared from 3-piperidin4-ylbenzamidine ditrifluoroacetate and 4-(6methoxypyridazin-3-yl)benzoic acid. 'H NMR (DMS0) 8 9.27 211), 8.90 211), 8.23 111), 8.13 (di, 211), 7.72-7.52 (in, 611), 7.30 (di, 111), 4.6 (br, 111), 4.08 311), 3.7 (br, 111, 3.2 (br, IM1, 2.9 (in, 2H1), 1.75 (in, 411. Ion spray MS 416.

r7- EXAMPLE 3-f 1,6-dlhydropyridazin-3-yl)benzoyl]-piperidin-4-ylbelzamfidile trifluoroacetate The title compound is prepared from 3 -piperidin-4-ylbenzamidine ditrifluoroacetate and 4-(6-oxo- 1,6dihydropyridazin-3-yl)benzoic acid. 'H NMR (DMSO) 8 13.2 111), 9.25 211), 8.98 211), 8.04 111), 7.90 211), 7.75-7.50 (in, 6H), 7.00 IM1, 4.6 (br, 111), 3.7 (br, 111), 3.2 (br, 111), 2.9 (mn, 211), 1.75 (mn, 4M1. Ion spray MS IvI+1: 402.

EXAMPLE 31 1-Aiinoisoguinolin-7-yl)piperidine-l1-carbonyllphenyl}lH1-pyridin-2-one trifluoroacetate A. 3-(4-Bromophenyl)acryloyl azide 4-Broinocinnainic acid (7.45 g, 32.8 inmol) dissolved in acetone (Il5OmL) and stirred under nitrogen at 0 *C during addition of triethylamnine (5.5 ml, 39.4 nimol), followed by ethyl chloroformate (3.76 ml, 39.4 mmol). Stirred reaction mixture at 0 "C for 1 hour, before adding a solution of sodium azide (3.19g, 49.2 nimol) in water (16 niL) dropwise. Stirred reaction mixture at 0 *C for 1 hour, then room temperature for 1 hour, before pouring into water (1 The white precipitate was collected and washed repeatedly with water and dried (high vacuum, P 2 0 5 to give 3-(4-broinophenyl)acryloyl azide (7.91 g, 31.3 mmol). 'H NMR (CDCI 3 8 7.66 (di, 111), 7.55 2117), 7.40 (di, 211), 6.41 1M1. ESI MS 251, 253 (Br).

B. 7-Bromo-2H-isoguinolin-I -one Preheated 2 separate oil baths to 240 A flask containing tributylamine (6.68 g, 36.1 inmol) and diphenyl ether (8OmL) was lowered into one oil bath and a flask containing 3-(4bromophenyl)acryloyl azide (7.91 g, 31.3 minol) and diphenyl ether (8OinL was lowered into the other oil bath [vigorous gas evolution internal temperature must quickly reach 200 After 10 minutes, the contents of flask B are poured into flask A, and the reaction left at 23 0-240 IC (internal temperature) for 30 minutes. Cooled reaction mixture to -100 poured into hexanes (2 LQ, stirred to WO 01/81310 PCT/US01/13810 -37cool to room temperature and filtered off the precipitate. Washed precipitate with methylene chloride hexanes (ratio 1/50), dried under high vacuum to give a colorless powder (4.20 g, 18.8 mmol). 1H NMR (DMSO) 8 11.41 1H), 8.23 1H), 7.82 (dd, 1H), 7.62 1H), 7.20 1H), 6.54 1H).

ESI MS 224,226 (Br).

C. 7-Bromo-1-chloroisoquinoline 7-Bromo-2H-isoquinolin-1-one (3.0 g, 13.4 mmol), phosphorus oxychloride (8.22 g, 53.6 mmol), and chloroform (25 mL) combined in a sealed tube and heated with stirring at 100 OC for 4 hours. Cooled to 60 poured into ice water (100 mL), neutralized carefully with saturated aqueous sodium 0 hydrogencarbonate, extracted into methylene chloride and dried over magnesium sulfate. Flash column chromatography on silica gel gave the product as a pale cream solid (2.01 g, 8.3 mmol). 'HNMR

(CDCI

3 8 8.51 1H), 8.30 1H), 7.82 (dd, 1H), 7.72 1H), 7.57 (dd, 1H). ESI MS 242, 244, 246 (Br, Cl).

D. I-Chloroisoquinolin-7-yl boronic acid 7-Bromo-l-chloroisoquinoline (1.38 g, 5.69 mmol) in THF (15 mL) under nitrogen, at -78 *C and triisopropyl borate (2.99 g, 15.93 mmol) added, followed by dropwise addition of n-butyllithium (7.11 mL of 1.6M in hexanes, 11.38 mmol). Allowed reaction mixture to warm to -20 OC over 30 minutes and quenched with 1N HCI (30 mL). Added triethylamine to give pH 7, presorbed solution directly 0 onto silica and flash column chromatography on silica gel to give the product as pale yellow solid (0.78 g, 3.8 mmol). 'H NMR (DMSO) 8 8.73 1H), 8.48 (brs, 2H), 8.35-8.28 1H), 8.25-8.13 (m, 1H), 8.06-7.92 1H), 7.91-7.82 1H). ESI MS 208, 210 (Cl).

E. 4-(1-Chloroisoquinolin-7-yl)-3,6-dihydro-2H-pyridine- -carboxylic acid tert-butyl ester 1-Chloroisoquinolin-7-yl boronic acid (0.55 g, 2.67 mmol), 4-(trifluoromethanesulfonyloxy)-3,6dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.68 g, 2.05 mmol), lithium chloride (0.26 g, 6.16 mmol), 2M aqueous sodium carbonate (2.9 ml, 5.8 mmol) and acetonitrile (15 mL) were combined under nitrogen, and palladium tetrakistriphenylphosphine (0.12 g, 0.103 mmol) added. The reaction mixture was refluxed for 90 minutes, cooled to room temperature, and concentrated in vacuo to give a wet solid. Ammonium hydroxide (3 mL of 30% aqueous solution) was added, and the material partitioned between methylene chloride (150 mL) and 2M aqueous sodium carbonate mL). The organic phase was separated, and the aqueous extracted successively with methylene chloride. The combined organic extracts were dried over magnesium sulfate, and purified by flash column chromatography on silica gel to give the product as a white solid (0.43 g, 1.25 mmol). 'H NMR (CDCI 3 5 8.26-8.20 2H), 7.88-7.75 2H), 7.57 1H), 6.28 (br s, 1H), 4.20-4.12 (m, 2H), 3.76 -3.66 2H), 2.75-2.62 2H), 1.56 9H). ESI MS 259, 261 (Cl).

WO 01/81310 PCT/US01/13810 -38ri F. 4-(1 -Aminoisoquinolin-7-yl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester trifluoroacetate 4-(1-Chloroisoquinolin-7-yl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester (0.10 g, 0.29 mmol), anhydrous ammonium acetate (0.23 g, 3 mmol), and phenol (0.36 g, 3.8 mmol) were combined into a sealed sample tube with venting capability (septa pierced several times), and heated (with stirring) at 100 OC for 28 hours. Cooled to room temperature, dissolved in acetonitrile water (50/50, 50 mL) and concentrated the solution down to dryness (repeated addition and concentration to azeotrope off phenol). Purified the crude by preparative reverse phase HPLC, and lyophilized the product to give an amorphous white solid (84 mg, 0.26 mmol). 'IH NMR (CDCl 3 8 7.88 1H1), 7.82- 7.78 1H), 7.67 1H), 7.57 1H), 6.96 1H), 6.22 (br s, 1H), 4.20-4.10 2H), 3.75-3.68 2H), 2.68-2.58 2H), 1.48 9H). ESI MS 326.

G. 7-(1,2,3,4-Tetrahydropyridin-4-yl)isoquinolin- I1-ylamine ditrifluoroacetate I-Aminoisoquinolin-7-yl)-3 ,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester trifluoroacetate (84 mg, 0.26 mnmol) was dissolved in methylene chloride (7.5 mL), and cooled at 0 OC during dropwise addition of trifluoroacetic acid (2.5 mL). After 1 hour at 0 OC the reaction mixture was concentrated to dryness and placed on high vacuum overnight to give the product as a pale yellow solid (87 mg, 0.26 mmol). 'H NMR (DMSO) 6 9.24-9.05 2H), 9.04-8.88 2H), 8.56 1H), 8.18-8.10 1H), 7.93 1H), 7.66 1H), 7.22 1H), 6.50 (br s, 1H), 3.90-3.78 2H), 3.52- 3.35 2H), 2.85-2.71 2H). ESI MS 226.

H. 7-Piperidin4-ylisoquinolin-1-ylamine ditrifluoroacetate 7-(1,2,3,4-Tetrahydropyridin-4-yl)isoquinolin-1-ylamine ditrifluoroacetate (87 mg, 0.26 mmol) dissolved in methanol (20 mL), added 5% palladium on carbon (10mg), and stirred at room temperature under an atmosphere of hydrogen (balloon) for 5 hours [NMR monitored to ensure no over-reduction]. The catalyst was filtered off, and the filtrate concentrated to give the product as a colorless solid (80 mg, 0.25 mmol).

'H NMR (DMSO) 8 8.90-8.71 1H), 8.60-8.42 1H), 8.38 1H), 7.96-7.84 2H), 7.66 (d, 7.20 1H11), 3.48-3.33 211), 3.17-2.93 3H), 2.13-2.02 2H1), 1.95-1.77 (min, 2H). ESI MS 228.

I. 4-(6-Methoxypyridin-3-yl)benzoic acid 4-Carboxybenzeneboronic acid (2.87 g, 17.3 mmol), 5-bromo-2-methoxypyridine (3.25g, 17.3 mmol), 0.4M aqueous sodium carbonate (87 ml, 34.8 mmol) and acetonitrile (86 mL) were combined under nitrogen, and palladium tetrakistriphenylphosphine (1.00 g, 0.87 mmol) added. The reaction mixture WO 01/81310 PCTIUS01/13810 -39- 0 was refluxed for 3 hours, cooled to room temperature, and filtered through celite (washed celite with 50:50 acetonitrile water). Removed acetonitrile in vacuo, diluted residue with water (I100mb) and acidified to pH 2 with 2M HC1. The precipitate which formed was collected, washed with water, and dried under high vacuum to give the product as a white powder (3.6 g, 15.7 mmol). 'H NMR (DMSO) 8 12.90 (br s, 111), 8.56 1H7), 8.08 (dd, 1M1, 7.98 211), 7.75 2H1), 6.94 lH), 3.90 3H1).

ESI MS 230.

J. 4-(6-Oxo-1,6-dihydropyridin-3-yl)benzoic acid 4-(6-Methoxypyridin-3-yl)benzoic acid (3.34 g, 14.6 mmol), dimethylsulfoxide (6 mL), and 0 pyridinium hydrochloride (8.43 g, 72.9 mmol) were heated together, with stirring, at 160 'C for minutes. The reaction mixture was cooled to 90 and water added slowly (I100mL). The solution/ suspension was cooled to 0 the precipitate filtered off and washed with water. The wet product was dried by azeotroping off the residual water with methanol to give the product as a white solid (2.38 g, 11.1 nimol). 'H NNvIR (DMS0) 8 7.93 2H1), 7.91-7.78 (in, 2M1, 7.68 2H1), 6.43 111). ESI MS 216.

K. 5- 1-Aminoisoguinolin-7-yl)piperidine- 1-carbonyllphenyl}- IH-pyridin-2-one trifluoroacetate 4-(6-Oxo- 1,6-dihydropyridin-3-yl)benzoic acid (25 mng, 0. 11 mmol) and diisopropylethylamine (57 mng, 0.44 mmol) were dissolved suspended in dimethylformamide (I mnL), and TBTU (3 5.6 mg, 0. 11 DO imol) added. Left solution stirring for 15 minutes before adding a solution of 7-piperidin-4ylisoquinolin-1-ylamine ditrifluoroacetate (50.5 mng, 0.11 mmol) and diisopropylethylamine (57 mng, 0.44 mmol) in dimethylformamide (1 mL). The reaction mixture was stirred at room temperature overnight, the solvent removed, and the residue purified by preparative reverse phase HPLC.

Lyophilization gave the product as an amorphous white powder (22.3 mg, 0.042 mmol). 'H NME.

(DMSO) 5 8.43 111), 7.98-7.80 (in, 311), 7.79-7.75 (in, 111', 7.70-7.56 (in, 7.46 211), 7.21 111), 6.42 111, 4.85-450 (in, 111), 4.10-4.00 (in, 111), 3.33-3.10 (in, 111), 3.09-2.94 (in, 2M1, 2.10-1.58 (in, 411). ESI MS 424.

EXAMPLE 32 1-Aminoisoguinolin-7-yl)piperidine- 1-carbonyl]- 1'H.[2,3 ']bipyridinyl-6 '-one trifluoroacetate A. 6-Methoxypyridin-3-ylboronic acid hydrochloride n-Butyllithium (13.1 mL of 1 .6M in hexanes, 21 ininol) was added dropwise to a stirring solution of bromo-2-methoxypyridine (3.76 g, 20 inmol) in THE (100 niL) at -100 'C under nitrogen. Left at this temperature for I hour, before adding triisopropylborate (11.28 g, 60 mm 01) and leaving the reaction to warm to room temperature overnight. Quenched with IN HCI (40 mL), and presorbed entire solution WO 01/81310 PCTfUS01/13810 directly onto silica and flash columned on silica gel. Gave product as a pale yellow powder (3.01 g, 16 mmol). 1H NMR (DMSO) 5 8.51 (di, 1IM, 8.08 (cd. 11), 6.85 1ff), 5.80 (br s, 211), 3.84 3H1). ESI MS 154.

B. 6-Bromonicotinic acid hydrochloride n-Butyllithium (8.0 mL. of 2.5M in hexanes, 20 mmol) was added dropwise to a stirring solution of (4.74 g, 20 mmol) in THF (100 mL) at -100 *C under nitrogen. Left at this temperature for 30 minutes, before bubbling anhydrous carbon dioxide gas through the reaction mixture (for 20 minutes), and leaving to warm to-20 0 Quenched with 1N HCI (20 mL) and brine niL), and extracted into ethyl acetate, dried over magnesium sulfate, concentrated to dryness. Gave product as a pale yellow powder (3.8 g, 16 mmol). 1H NMR (CDC1 3 4-MeOll) 8 8.86 (di, IlH), 8.07 (cid, IM1, 7.52 IH). ESI MS 202, 204.

C. 6'-Methoxy[2,3 ']bipyridinyl-5-carboxylic acid The title compound is prepared as described in EXAMIPLE 3 1, Part 1, but with 6-bromonicotinic acid hydrochloride and 6-naethoxypyridin-3-ylboronic acid hydrochloride as starting materials, and molar equivalents of 0.4M aqueous sodium carbonate. 'H NMR (DMSO) 8 13.40 (br s, 111), 9. 10 (di, 111), 8.95 IM1, 8.43 (dd, 111), 8.28 (dd, 111), 8.09 6.95 (di, 111), 3.91 3M1. ESI MS 23 1.

D. 6'-Oxo-1 ',6'-dihydro-[2,3 ']bipyridinyl-5-carboxylic acid The title compound is prepared as described in EXAMPLE 3 1, Part J, but with 6'methoxy[2,3']bipyridinyl-5-carboxylic acid as starting material. 'H NMR (DMS0) 8 13.00 (br s, 114), 12.10 (br s, 1H1), 8.99 111), 8.3 1-8.12 (in, 3H1), 7.91 1M1, 6.42 111). ESI MS 217.

E. 5-I!4-(1 -Aminoisoguinolin-7-yl)piperidine-lI-carbonyl]-l1'H-[2,3 ']bipyridinyl-6'-one trifluoroacetate The title compound is prepared as described in EXAMAPLE 3 1, Part K, but with 6'-oxo- 1',6'-dihydro- [2,3']bipyridinyl-5-carboxylic acid as starting material. 1H NMR (DMSO) 8 13.08 (br s, 111), 12.00 (br s, 111), 9.00 (br s, 2H1), 8.63 111), 8.43 1H), 8.24-8.16 (in, 2ff, 7.98-7.82 (mn, 411), 7.60 111), 7.19 111), 6.43 (di, 111), 4.72-4.56 (in, IM1, 3.79-3.64 (mn, 111), 3.35-3.21 (in, 1H4), 3.10-2.86 (in, 21-1), 2.00-1.61 (mn, 41D). ESI MS 426.

EXAMPLE 33 F 1-Aminoisoguinolin-7-yl)piperidin-1I-yl f2-fluoro-4-(6-methoxyIpyridin-3-yl~phenyllmeffianone trifluoroacetate A. 2-Fluoro-4-(6-methoxypyridin-3-yl)benzoic acid WO 01/81310 PCT[US01/13810 -41- The title compound is prepared as described in EXAMPLE 3 1, Part I, but with 4-bromo-2fluorobeazoic acid and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and molar equivalents of 0.4M aqueous sodium carbonate. 1H NMR (DMSO) 8 13.30 (br s, IM, 8.59 (di, 11), 8.11 (dci, 111), 7.90 1K), 7.68-7.57 (in, 211), 6.91 111), 3.88 3H1). ES! MS 248.

B. -Aniinoisoquinolin-7-yl)piperidin-1I-yl]F2-fluoro-4-(6-methoxypyridin-3-yl)phenyllmethanone __trifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 2-fluoro-4-(6inethoxypyridin-3-yl)benzoic acid as starting material. 'H1 NMdR (DMSO) 8 9.08-8.85 (mn, 2H1), 8.5 8 (di, 0 1H), 8.42 (ci, 111), 8.15-8.05 (in, 111), 7.91 211), 7.72-7.58 (mn, 3H1), 7.55-7.44 (mn, 1K), 7.20 (ci, 111), 6.93 (di, 111), 4.80-4.65 (in, 1IM, 3.88 311), 3.68-3.51 (in, 111), 3.33-3.15 (mn, lIH); 3.12 (mn, 211), 2.05-1.50 (in, 411). ESI MS 457.

EXAMPLE 34 r4- 1 -Aninoisoguinolin-7-yl)piperidin-1 -yl](2-fluoro-4-pyridin-3-ylphenyl)inethanone ditrifluoroacetate A. 2-Fluoro-4-pyridin-3-ylbenzoic acid The title compound is prepared as described in EXAMPLE 3 1, Part I, but with 4-bromo-2fluorobenzoic acid and 3-pyridinylboronic acid as starting materials. 'H NMR (DM50) 8 8.97 1K), .0 8.66-8.58 (in, 111), 8.22-8.12 (in, 111, 8.00-7.91 (mn, 111), 7.81-7.62 (in, 211), 7.55-7.45 (mn, 1II). ESI MS 218.

B. I-Aininoisoquinolin-7-yI)piperidin- 1-yl3(2-fluoro-4-pyridin-3-ylphenyl)methanone ditrifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 2-fluoro-4-pyridin-3ylbenzoic acid as starting material. 'H NMIR (DMSO) 8 9.02 111), 8.66 (di, 111), 8.42 111), 8.26 (di, 111), 7.98-7.86 (in, 211), 7.84-7.66 (in, 211), 7.64-7.50 (mn, 311), 7.20 (di, 111), 4.72 111), 3.65-3.52 (in, 111), 3.35-3.18 (in, 111), 3.12-2.86 (in, 211), 2.03-1.55 (mn, 411). ESI MS 427.

EXAMPLE 4 I-Aminoisoguinolin-7-yl)piperidine- I-carbonyllbiphenyl-3-carboxylic acid amide trifluoroacetate A. 3 '-Carbanioylbiphenyl-4-carboxylic acid The title compound is prepared as described in EXAMPLE 3 1, Part I, but with 3-broniobenzene carboxamide as starting material. 111NNER (DMSO) 8 8.20 111), 8.12 111), 8.03 (ci, 2H1), 7.93- 7.80 (in, 4M1, 7.61-7.52 (mn, 111), 7.48-7.43 (br s, 111). ES! MS 242.

WO 01/81310 PCT[US01/13810 -42- B. -Aminoisoquinolin-7-yl)piperidine- l-carbonyllbiphenyl-3-carboxylic acid amide trifluoroacetate The title compound is prepared as described in EXAMPLE 31, Part K, but with 3'-carbamoylbiphenyl- 4-carboxylic acid as starting material. 'H NMR(DMSO) 5 8.43 11), 8.18 11), 7.96-7.78 (m, 6H), 7.65-7.50 4H), 7.43 1f), 7.21 1H), 4.80-4.60 11), 3.92-3.70 11), 3.35-3.15 INH), 3.10-2.83 21), 2.03-1.55 41). ESI MS 451.

EXAMPLE 36 [4-(1-Am inoisoguinolin-7-yl)piperidin- 1-yll [5-(6-iethoxypyridin-3-yI)thiophen-2-yll]lmethanone trifluoroacetate A. 5-(6-Methoxypyridin-3-yl)thiophene-2-carboxylic acid The title compound is prepared as described in EXAMPLE 31, Part I, but with 5-bromothiophene-2carboxylic acid and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and molar equivalents of 0.4M aqueous sodium carbonate. 'H NMR (DMSO) 5 13.10 (br s, 11), 8.55 (d, IN), 8.03 (dd, 7.66 11), 7.50 111), 6.90 11). ESI MS 236.

B. -Aminoisoquinolin-7-yl)piperidin- 1-yl] [5-(6-methoxypyridin-3-yl)thiophen-2-ylijmethanone trifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 5-(6-methoxypyridin- 3-yl)thiophene-2-carboxylic acid as starting material. 1H NMR (DMSO) 8 13.30 (br s, 11), 9.06 (br s, 2H), 8.52 11), 8.44 8.02 (dd, 11), 7.95-7.87 21), 7.60 11), 7.49-7.43 2H), 7.18 1H), 6.89 1H), 4.52-4.42 21), 3.87 3H), 3.28-3.01 3H), 1.96-1.88 21), 1.77-1.60 2H). ESI MS 445.

EXAMPLE 37 5-{4-[4-(I-Aminoisouinolin-7-yl)piperidine- -carbonylj-3-fluorophenyl)-1 H-pyridin-2-one trifluoroacetate A. 2-FIuoro-4-(6-oxo-1 ,6-dihydropyridin-3-yl)benzoic acid The title compound is prepared as described in EXAMPLE 31, Part J, but with 2-fluoro-4-(6methoxypyridin-3-yl)benzoic acid as starting material. 'H NMR (DMSO) 8 13.25 (br s, 11), 12.10 (br s, 114), 7.96-7.88 21), 7.84 11), 7.58-7.47 21), 6.42 1H). ESI MS 234.

B. 5-{4-[4-(1-Aiinoisoguinolin-7-yl)piperidine-1-carbonyll-3-fluoropbenyl}-lH-pyridin-2-one trifluoroacetate WO 01/81310 PCTfUS01/13810 -43- 0The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 2-fluoro-4-(6-oxo-1,6dihydropyridin-3-yl)benzoic acid as starting material. 'H NUR (DMS0) 8 13.12 (hr s, 11H), 11.96 (hr s, 111), 9.02 (br s, 2H1), 8.41 1H), 7.95-7.82 (in, 4117), 7.63-7.40 (in, 4H), 7.19 1H1), 6.42 (di, 1M1, 4.74-4.66 (in, 111), 3.60-3.51 (in, 111), 3.32-3.20 (in, 111), 3.08-2.87 (mn, 2H1), 2.02-1.55 (in, 41H). ESI MS 443.

EXAMPLE 38 1-Am inoisoquinolin-7-yl)piperidine- vabonyllthiophen-2-yl H-pyridin-2-one trifluoroacetate 0 A. 5-(6-Oxo-1,6-dihydropyridin-3-yl)thiophene-2-caboxylic acid The title compound is prepared as described in EXAMIPLE 3 1, Part J, but with 5-(6-methoxypyridin-3yl)thiophene-2-carboxylic acid as starting material. 'H NUR (DMSO) 5 13.00 (br s, 11H), 12.10 (hr s, 1W), 7.84 11W), 7.78 (dd, 111, 7.63 11-17), 7.36 111), 6.41 111). £51 MIS (MI1) 222.

B. 5- 1-Aminoisoguinolin-7-yl)piperidine-1 -carbonyllthiophen-2-yl} IH-pyridin-2-one trifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 5-(6-oxo- 1,6dihydropyridin-3-yl)thiophene-2-carboxylic acid~as starting material. 'H NMR (DMSO) 8 13.11 (hr s, 11.96 (br s, 1W),'8.98 (hr s, 1IM', 8.43 1H1), 7.95-7.87 (in, 2H), 7.80-7.74 (mn, 211), 7.61 1H1), .0 7.39 1WH), 7.31 111), 7.19 (di, 111), 6.41 11), 4.52-4.42 (mn, 2H), 3.26-3.00 (in, 311), 1.98-1.88 (mn, 2H), 1.82-1.67 (mn, 2H1). E51 MS 43 1.

EXAMPLE 39 I-Aminoisoguinolin-7-yl)-3 ,6-dihydro-2H-pyridine-l1-carbonylllphenyl} -1H-pyridin-2-one trifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 7-(1,2,3,4tetrahydropyridin-4-yl)isoquinolin-1I-ylamine ditrifluoroacetate as starting material. 'H NMRA (DMSO) 8 8.52 111), 8.18-8.05 (in, 111), 7.98-7.83 (in, 311), 7.80 111, 7.71-7.63 (mn, 311), 7.47 (di, 211), 7.22 111, 6.65-6.35 (in, 211), 4.41-4.15 (in, 211, 3.95-3.55 (mn, 211), 2.85-2.73 (in, 2H1). ESI MS 423.

EXAMPLE I-Aniinoisoguinolin-7-yl)-3 ,6-dihydro-211-pyridin- 1-yll(4-.p Wiin-4ypey~ehnn ditrifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 7-(1 ,2,3,4tetrabydropyridin-4-yl)isoquinol in-I1 -ylamine ditrifluoroadetate and 4-pyridin-4-ylbenzoic acid as WO 01/81310 PCTIUSOI/13810 -44starting materials. 'H NMR (DMSO) 8 8.82-8.70 (in, 1H), 8.53 1117), 8.18-8.05 (in, 111), 8.03-7.83 (mn, 6H), 7.65 2H), 7.22 111), 6.64-6.31 (mn, 11-17), 4.42-4.38 (mn, 211), 4.3 6-4. 10 (in, 211), 2.78- 2.63 (mn, 2H1). ES! MS (M+1I) 407.

EXAMPLE 41 [4.(-mniounln7-lRprd1y]4-(6mtoy *d--lpenlm trifluoroacetate The title compound is prepared as described in EXAM4PLE 3 1, Part K, but with 4-(6-methoxypyridin- 3-yl)benzoic acid as starting material. 1H NMvR (DMS0) 5 8.53 I11, 8.43 I 8.08-8.02 (mn, 1H1), 7.98-7.87 (mn, 211), 7.76 211), 7.63 111), 7.53 2117, 7.21 111), 6.92 111), 4.68 (br s, 1K), 3.87 3H1), 3.35-3.13 (mn, 114), 3.11-2.85 (in, 211), 2.03-1.60 (in, 411). ESI MIS 439.

EXAMPLE 42 1-Am jnoisoguinolin-7-yl)piperidin- 1-yl](4-pyridin-3-ylphenyl)methanone ditrifluoroacetate The title compound is prepared as described in EXAMIPLE 3 1, Part K, but with 4-pyridin-3-ylbenzoic acid as starting material. 114NMR (DMSO) 8 8.83 111), 8.62 111), 8.45 IM, 8.18 111), 7.98-7.87 (in, 411), 7.66-7.50 (in, 411, 7.22 111), 4.80-4.61 (mn, 111), 3.88-3.70 (mn, 111), 3.32-3.15 (mn, 111), 3.10-2.85 (in, 211), 2.04-1.60 (mn, 4117). ES! MS 409.

EXAMPLE 43 r4-( 1-Aminoisoguinolin-7-yl)piperidin- 1-yl](6'-methoxy-[2,3 ditrifluoroacetate The title compound is prepared as described in EXAMPLE 3 1, Part K, but with 6'methoxy[2,3']bipyridinyl-5-carboxylic acid as starting material. 1 H NMvR (DMSO) 8 8.91 111), 8.73 111), 8.48-8.3 8 (mn, 211, 8.07 111), 8.00-7.87 (mn, 311', 7.60 111), 7.22 111, 6.96 111), 4.80-4.60 (in, 111), 3.91 3H1), 3.80-3.71 (mn, 111), 3.35-3.20 (mn, 111), 3.13-2.85 (in, 211), 2.01-1.65 (in, 41-1). ESI MS 440.

EXAMIPLE 44 5- {4-r4-(4-Amino- 1H-pyrrolo[3,2-clpyridin-2-yl)piperidine- 1-carbonyllphenyl} lH-pyridin-2-one trifluoroacetate A. (2-Chloropyridin4yl)carbaniic acid tert-butyl ese Sodium bis(trimethylsilyl)amide (90 mL of IM in THF, 90 nimol) was added slowly to a stirring solution of 4-amino-2-chloropyridine (5.79 g, 45 minol) in THF (100 mL) at room temperature under nitrogen. Left at room temperature for 15 minutes before adding dropwise a solution of di-tert-butyl dicarbonate (8.95 g, 41 minol) in TE (50 mL). After 2 hours the solvent was removed in vacuo, and WO 01/81310 PCT/US01/13810 O 0.1N HCI (100 mL) added to the residue, and extracted with ethyl acetate. Washed ethyl acetate with 0.1N HC1, dried organics over magnesium sulfate, and concentrated to dryness. The slightly crude yellow solid was washed with cold diethyl ether (3 x 20 mL) to give the pure product as a cream solid (6.43 g, 28 mmol). H NMR (CDCI 3 5 8.17 1H), 7.49 1H), 7.15 (dd, 1H), 6.95 (br s, 1H), 1.51 9H). ESI MS 229, 331 S B. (2-Chloro-3-methylpyridin-4-yl)carbamic acid tert-butyl ester r tert-Butyllithium (29 mL of 1.7M in pentane, 50 mmol) was added dropwise to a vigorously stirring solution of(2-chloropyridin-4-yl)carbamic acid tert-butyl ester (4.57 g, 20 mmol) in THF (150 mL) at -78 °C under nitrogen. The reaction mixture was kept at this temperature for 4 hours before adding a solution of methyl iodide (3.41 g, 24 mmol) in THF (20 mL). Warmed the reaction mixture to 0 *C over 2 hours, and quenched the reaction with saturated aqueous ammonium chloride solution (100 mL). Extracted into ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to dryness. Flash column chromatography on silica gel gave the product as a white solid (2.93 g, 12 mmol). H NMR (CDCI3) 5 8.11 1H), 7.98 1H), 6.58 (br s, 1H), 2.30 3H), 1.52 9H). ESI MS 243, 245 (Cl).

C. 4-(Methoxymethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9.20 g, 48 mmol) was added to a stirring solution of 1-tert-butoxycarbonylisonipecotic acid (10.0 g, 43.6 mmol) in methylene chloride (200 mL) at 0 under nitrogen. After 5 minutes at this temperature N, O-dimethylhydroxylamine hydrochloride was added, followed by the dropwise addition of pyridine (11.39 g, 144 mmol).

Warmed the reaction mixture to room temperature, and stirred for 3 hours before quenching with 1N HCI (100 mL). The organic phase was separated and washed with 1N HCI (2 x 100 mL), followed by saturated aqueous sodium hydrogencarbonate (2 x 100 mL). The organics were dried over magnesium sulfate and concentrated to dryness, to give the product as a colorless oil (8.61 g, 31.6 mmol). 'H NMR

(CDC

3 5 4.15-4.04 2H), 3.68 3H), 3.15 3H), 2.82-2.56 3H), 1.73-1.58 4H), 1.42 (s, 9H). ESI MS 273.

D. 4-Chloro-2-piperidin-4-yl- 1H-pyrrolo[3,2-c]pyridine n-Butyllithium (3.36 mL of 2.5M in hexanes, 8.4 mmol) was added dropwise to a stirring solution of (2-chloro-3-methylpyridin-4-yl)carbamic acid tert-butyl ester (0.971 g, 4 mmol) in THF (50 mL) at 78 under nitrogen. Warmed the reaction mixture to -20 OC for 15 minutes, before cooling back to 78 C and adding a solution of 4-(methoxymethylcarbamoyl)piperidine-l-carboxylic acid tert-butyl ester (1.089 g, 4 mmol) in THF (10 mL). Warmed the reaction slowly to room temperature over 2 hours, and quenched with IN HCI (50 mL). Extracted into ethyl acetate, washed with saturated WO 01/81310 PCT[US01/13810 -46aqueous sodium hydrogencarbonate, and dried over magnesium sulfate. Flash column chromatography gave a 1: 1 mixture, by NMR, of the ring open and ring closed tautomers of the required intermediate {4-[(tert-butoxycarbonylamino-2-chloropyridin-3-yl)acety]piperidine- 1-carboxylic acid tert-butyl ester and 1-tert-butoxycarbonylpiperidin-4yl-4-chloro-2-hydroxy-2,3-dihydropyrrolo[3,2c]pyridiue-l-carboxylic acid tert-butyl ester). This material (845 mg, 1.88 minol) was dissolved in methylene chloride (40 niL) and stirred vigorously at room temperature during the dropwise addition of trifluoroacetic acid (4 mL). After 2 hours the reaction mixture was concentrated to dryness, and flash column chromatographed on silica gel with ammonium hydroxide methylene chlorideI methanol to give the pure fr-ee base product as a white powder (420 mg, 1.76 mmol). 'H NMR (d 4 MeOH) 8 7.87 1H1), 731 111), 6.39 111), 3.52-3.45 (in, 2H4), 3.20-3.09 (in, 3H1), 2.36-2.25 (in, 211), 2.04-1.88 (in, 211). ESI MS 236, 23 8 (Ql.

E. 5- {4-[4-(4-Chloro- 1H-pyrrolo[3 ,2-c]pyidin-2-yl)piperidine-lI-carbonyllphenyl)- lH-pyridin-2-one The title compound is prepared as described in EXAMAPLE 3 1, Part K, but with 4-chloro-2-piperidin- 4-yI-IH-pyrrolo[3,2-c]pyridine and 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoic acid as starting materials. Purification was by flash column chromatography on silica gel. 1H1 NMR (d 4 -MeOH) 8 7.99 (dd, 111), 7.87 111), 7.77 1H1), 7.66-7.63 (in, 21-I), 7.54-7.50 (mn, 211), 7.30 (dd, 111), 6.65 111), 6.41 1M1, 3.96-3.84 (in, 1H1), 3.45-3.05 (mn, 4H), 2.22-2.01 (in, 211), 1.92-1.71 (in, 211). ESI MS F. 5- (4-(4-(4-Amino- lH-pyrrolo[3,2-clpyridin-2-yl)piperidine- 1-carbonyllphenyl} H-pyridin-2-one trifluoroacetate The title compound is prepared as described in EXAMPLE 31, Part F, but with 5-{4-[4-(4-chloro-1Hpyrrolo[3,2-c]pyridin-2-yl)piperidine- 1 -carbonyl]phenyl} IH-pyridin-2-one as the starting material.

Heated (with stirring) at 110 IC for 4 days to obtain complete conversion. 'H NMR (d 4 -MeOH) 5 7.98 (dd, 111, 7.78 111), 7.67-7.61 (mn, 211, 7.54-7.49 (mn, 211), 7.40 111), 6.93 IM1, 6.70-6.48 (in, 211), 4.83-4.70 (mn, 111), 3.99-3.84 (mn, 1Hi), 3.40-3.01 (mn, 311), 2.24-1.95 (in, 2M1, 1.90-1.65 (in, 211).

ESI MS (M+1) 4 414.

5-[4-(4-Ainino- lH-pyrrolotl3,2-clpyridin-2-yl)piperidine-l-carbonyl]-1 ']bipyridinyl-6'-one trifluoroacetate The title compound is prepared as described in EXAMPLE 44, parts A and B, but with 6'-oxo- dihydro-[2,3 'Jbipyridinyl-5-carboxylic acid, and 5- [4-(4-chloro- lH-pyrrolo[3,2-c]pyridin-2yl)piperidine- 1-carbonyl]- 1 'lbipyridinyl-6 '-one trifluoroacetate as starting materials, respectively. NR (d 4 -MeOH) 5 8.67-8.65 (in, 111), 8.32 (dd, 111), 8.25 111'), 7.92 (dd, 111), WO 01/81310 PCT[US01/13810 -47- O 7.85 (dd, 1H), 7.40 1H), 6.94 1H), 6.68-6.63 2H), 4.85-4.70 1H), 3.99-3.82 1H), 3.42-3.03 3H), 2.24-2.06 2H), 1.88-1.68 2H). ESI MS 415.

EXAMPLE 46 1 -(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzamidine hydrochloride A. 3-(Piperidin-4-yl)-benzonitrile A solution of lithium diisopropylamine (54 mmol) in anhydrous tetrahydrofuran (50 ml) at -78 OC is treated dropwise with a solution of benzyl 4-oxo-l-piperidinecarboxylate (11.4 g, 49 mmol) in anhydrous tetrahydrofuran (50 ml). The reaction mixture is then stirred a further 20 min. at -78 OC and S0 treated with a solution of N-phenyltrifluoromethanesulfonimide (19.26 g, 54 mmol) in anhydrous tetrahydrofuran (55 ml). The resultant orange suspension is warmed to 0 °C and stirred for 2 hours before being concentrated under vacuum. The residue is chromatographed on silica gel (CH 2

C

2 to yield benzyl 1,2,3,6-tetrahydro-4-(trifluoromethylsulphonyloxy)-pyridine--carboxylate as a yellow oil (11.34 A portion of this material (3.65 g, 10 mmol) is dissolved in anhydrous 1,2-dimethoxyethane (30 ml) and treated with 3-cyanophenyl boronic acid (1.47 g, 10 mmol), lithium chloride (1.27 g, mmol), 2.0 M aqueous sodium carbonate (10 ml) and palladium tetrakistriphenylphosphine (0.73 g, 0.6 mmol). The reaction mixture is heated at reflux for 2.5 hours, cooled and concentrated under vacuum.

The residue is partitioned between dichloromethane (2 X 100 ml) and 2.0M aqueous sodium carbonate (100 ml) containing cone ammonium hydroxide (6 ml). The combined organic extracts are dried 0 (magnesium sulfate), concentrated under vacuum and the resultant oil is chromatographed on silica gel (ethyl acetate/pentane 2:5) to yield a yellow oil (2.31 This material is dissolved in ethanol (70 ml), treated with 10% palladium on carbon (1.0 g) and stirred at ambient temperature under an atmosphere of hydrogen for 5 hours. The reaction mixture is filtered through a short pad of hyflo and concentrated under vacuum to give the title compound as a colourless oil (1.26 1 H NMR (CDCl 3 500 MHz) 89.78 (br m, 1H), 7.50 4H), 4.49 (br m, 1H), 3.65 (br m, 1H), 3.00 2H), 2.82 (m, 1H), 2.21-1.75 4H). El MS 187.

B. 3- 1-(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzonitrile A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.75 g, 3.3 mmol) in anhydrous dimethylformamide (9 ml) is treated with HATU (1.27 g, 3.3 mmol) and diisopropylethylamine (1.1 ml, 6.1 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(piperidin-4-yl)-benzonitrile (0.6 g, 3 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at ambient temperature 2 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ((45 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give the title compound as a yellow WO 01/81310 PCT[S01/13810 -48oil (0.53 'H NMR (CDCIl, 500 MHz) 88.80 1H), 8.63 1H), 8.00 1H), 7.50 9H), 4.90 (br m, 1H), 3.85 (br m, 1H), 328 1H), 2.90 2H), 1.91 1H), 1.75 3H). El MS M++H: 392.

C. 3-[1-(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl-benzamidine hydrochloride A solution of 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzonitrile (0.51 g, 1.3 mmol) in methanol (20 ml) is cooled to 0 OC and saturated with hydrogen chloride gas. The reaction vessel is sealed and allowed to stand at 0 OC for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (20 ml) and cooled to 0 OC. The solution is saturated with ammonia gas and the vessel sealed before being allowed to stand at 0 OC for 48 hours. The reaction mixture is concentrated to dryness under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 9:1) to give the title compound as a light yellow amorphous solid (0.42 'HNMR (DMSO, 500 MHz) 88.85 1H), 8.67 1H), 8.08 1H), 7.75 1H), 7.67 2H), 7.62 2H), 7.56 (mi, 1H), 7.48 2H), 7.47 1H), 4.67 (br m, 1H), 3.65 (br m, 1H), 2.94 (m, 3H), 1.96 1H), 1.68 3H). EI MS M+H: 409.

EXAMPLE 47 3-r1-(5-Phenylethynyl-pyridine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-benzamidine hydrochloride A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.46 g, 2.1 mmol) in anhydrous dimethylformamide (7 ml) is treated with HATU (0.78 g, 2.1 mmol) and diisopropylethylamine (0.98 ml, 5.6 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(1,2,3,6-tetrahydropyridin- 4-yl)-benzonitrile (1.9 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at.ambient temperature 3 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give pyridine-3-carbonyl)-l,2,3,6-tetrahydropyridin-4-yl]-benzonitrile as a yellow oil (0.23 This material is dissolved in methanol (15 ml), cooled to 0 °C and saturated with hydrogen chloride gas.

The reaction vessel is sealed and allowed to stand at 0 *C for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (15 ml) and cooled to 0 OC. The solution is saturated with ammonia gas and the vessel sealed before being allowed to stand at 0 *C for 48 hours. The reaction mixture is concentrated to dryness under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 9:1) to give the title compound as a yellow amorphous solid (0.2 'H NMR (DMSO, 500 MHz) 88.85 1H), 8.67 1H), 8.10 1H), 7.85 (s, WO 01/81310 PCT[US01/13810 -49- 111H), 7.80 (in, 1H), 7.75 (in, 111), 7.60 (mn, 311), 7.48 (in, 3H1), 6.38 (mn, 111), 4.38 (br mn, IM, 4.19 (hr m, 111), 3.90 (br mn, 111), 3.60 (br mn, 111), 2.63 (br m, 2H1). El MS M 4 407.

EXAMPLE 48 3-[1-(5-Phenylethyl-pyridine-3-carbonyl)-piperidin4-yl-benzamidiie hydrochloride A solution of 1-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzanidile hydrochloride (Example 46) (150 ing) in ethanol (5 ml), treated with 10% palladium on carbon (15 mg) and stirred at ambient temperature under an atmosphere of hydrogen for 5 hours. The reaction mixture is filtered through a short pad of hyflo and concentrated under vacuum to give the title compound as a colourless oil (150 mng). 1H NMR (DMS0, 500 MHz) 58.48 (in, 2H1), 7.78 111, 7.65 (in, 3H1), 7.59 (mn, I1H), 7.20 (mn, 511), 4.63 (hr m, 111), 3.57 (br mn, 1H1), 3.18 (br m, 111), 2.90 (in, 611), 1.70-1.90 (br m, 411).

El MS 413.

EXAMPLE 49 3-(4-(5-Phenylethyl-pyridine-3-carbonyl)-piperazin- 1-yl]-benzamidine di-bydrochloride A. 1 -(3-Cyanophenyl)piperazine A mixture of 3-fluorobenzonitrile (3.0 g, 25 iniol), piperazine (11.8 g, 137 mmol) and dimethylsulphoxide (20 ml) is heated at 100 TC for 48 hours under an atmosphere of nitrogen. The reaction mixture is then cooled, poured into water (200 ml) and the resultant precipitate collected.

zO Th~is solid is chromatographed on silica gel (dichloromethane) to give the title compound as a white solid (6.7 1H NMvR (DMS0, 500 M91z) 87.15-7.40 (in, 411), 3.28 (in, 311), 3.12 (in, 1H), 2.80 (mn, 111), 2.59 (in, 311).

B. 34[4-(5-Phenylethyl-pyridine-3-carbonyl)-piperazin- 1-yll-benzonitrile A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.4 g, 1.8 inmol) in anhydrous diinethylforinanide (3 ml) is treated with HATU (0.7 g, 1.8 inmol) and diisopropylethylamine (0.6 ml, 3.3 mmnol). The reaction mixture is stirred 10 inins. at ambient temperature before being treated with a solution of 1-(3-cyanophenyl)piperazine (0.3 g, 1.6 iniol) in diinethylforminide (5 ml). The reaction mixture is stirred at ambient temperature for 18 hours, concentrated under vacuum and the residue partitioned between dichloromethane (2 X 40 ml) and saturated aqueous sodium bicarbonate ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chroinatographed on silica gel (ethyl acetate) to give the title compound as a yellow oil (0.33 1H NMR (CDCI 3 500 MHz) 88.82 111), 8.61 111), 7.90 111), 7.58 (in, 211), 7.39 (in, 411, 7.16 (in, 3H1), 3.95 (br mn, 2H1), 3.63 (hr mn, 211), 3.30 (hr mn, 411). El MS Mi+H: 393.

C. 3-4(-hnlty-ydne3croy)pprz 1 -y1]-benzamidine hydrochloride WO 01/81310 PCT/US01/13810 A solution of 3-[l-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzonitrile (0.32 g, 0.8 mmol) in methanol (20 ml) is cooled to 0 OC and saturated with hydrogen chloride gas. The reaction vessel is sealed and allowed to stand at 0 OC for 18 hours. The reaction mixture is concentrated to dryness under vacuum, redissolved in methanol (20 ml) and cooled to 0 OC. The solution is saturated with ammonia gas and the vessel sealed before being allowed to stand at 0 °C for 48 hours. The.

reaction mixture was concentrated to dryness under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 4:1) to give the title compound as a yellow amorphous solid (45 mg).

'HNMR (DMSO, 500 MHz) 89.25 (br s, 1H), 8,92 (br s 1H), 8.85 1H), 8.65 1H), 8.10 1H), 7.60 2H), 7.45 4H), 7.32 2H), 7.20 1H), 3.80 (br m, 2H), 3.52 (br m, 2H), 3.30-3.40 (br m, 4H). EI MS M+H: 410.

WO 01/81310 PCT[US01/13810 -51- By the methods described above, the following compounds are made: NHNNN

N

NH N NH2

NHN

N NH 2 NH 2 -H N NH 2

H-

NNNN

N

O -KR 3 NH -N N NH N NH 2

NH

2 -N NH 2

H-N

N N N N I~ NR I~ R and Oj KR wherein R 3 is selected from the group consisting of

KN-

0 NH 2 0 NH 2

NH

2 NMe 2

NH

2 0 2

N

0 1 /1 NH 2

NO

N N N 1 H2N S' WO 01/81310 WO 0181310PCT/USOI/13810 -52-

I-

S

~'S

1,NH?.

-~1 -~1 018fl/losfi/lad 0HC18110 OAA WO 01/81310 PCT[S01/13810 -54- 'S S S

,N

I 0-

NN

N/ N and The molecules described herein inhibit blood coagulation by virtue of their ability to inhibit the penultimate enzyme in the coagulation cascade, factor Xa, rather than thrombin. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin Il.

Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature.

The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal WO 01/81310 PCT/US01/13810 O narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening thrombin throughout the microvasculature of O several organ systems. The indications discussed above include some, but not all, of the possible 10 clinical situations where anticoagulant therapy is warranted. Those experienced in this field are well Saware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.

The compounds described herein may be administered to treat thrombotic complications in a variety of animals such as primates including humans, sheep, horses, cattle, pigs, dogs, rats and mice.

Inhibition of factor Xa is useful not only in the anticoagulant therapy of individuals having thrombotic conditions but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus, any factor Xa inhibitor can be added to or contacted with any medium containing or suspected of containing factor Xa and in which it is desired that blood coagulation be inhibited.

In addition to their use in anticoagulant therapy, factor Xa inhibitors may find utility in the treatment or prevention of other diseases in which the generation of thrombin has been implicated as playing a pathologic role. For example, thrombin has been proposed to contribute to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis and Alzheimer's disease by virtue of its ability to regulate many different cell types through specific cleavage and activation of a cell surface thrombin receptor. Inhibition of factor Xa will effectively block thrombin generation and therefore neutralize any pathologic effects of thrombin on various cell types.

Accordingly, the invention provides a method of inhibiting factor Xa comprising contacting a factor Xa inhibitory amount of a compound of formula I with a composition containing Factor Xa.

According to a further feature of the invention there is provided a method of inhibiting the formation of thrombin comprising contacting Factor Xa inhibitory amount of a compound of formula I with a composition containing Factor Xa.

According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa, for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of formula I or a composition containing a compound of formula I.

WO 01/81310 PCT[US01/13810 -56- The compounds of formula I may be used alone or in combination with other diagnostic, cardioprotective agents, direct thrombin inhibitors, anticoagulants, antiplatelet or fibrinolytic agents, selected from: anti-coagulants such as warfarin, heparin or low molecular weight heparin; synthetic pentasaccharides; anti-platelet agents such as aspirin, piroxicam or ticlopidine; direct thrombin inhibitors boroarginine derivatives, hirudin or argatroban (Novastan)); fibrinogen receptor antagonists; statins fibrates; or fibrinolytic agents (thrombolytic agents) such as tissue plasminogen activator, anistreplase (Eminase), urokinase or streptokinase, Factor Xa inhibitors or Factor VIIa inhibitors; or combinations thereof. Often patients are concurrently treated prior, during and after interventional procedures with agents of these classes either in order to safely perform the interventional procedure or to prevent deleterious effects of thrombus formation.

The term "cardioprotective agents" as used herein, denotes agents that act to protect myocardium during ischemia. These cardioprotective agents include, but are nor limited to, adenosine agonists, P-blockers and Na/H exchange inhibitors. Adendosine agonists include those compounds disclosed in Spada et al., US Patent No. 5,364,862 and Spada et al., US Patent No. 5,736,554, the disclosures of which are hereby incorporated herein by reference. An example of an adenosine agonists is AMP 579 (Rhone-Poulenc Rorer). An example of a Na/H exchange inhibitor is Cariporide (HOE 642).

The term "anti-coagulant agents" as used herein, denotes agents that inhibit blood coagulation.

Such agents include warfarin (Coumadin®) and heparin.

The term "anti-platelet 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 the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam (Feldanee), including pharmaceutically acceptable salts or prodrugs thereof. Other suitable antiplatelet agents include ticlopidine (Ticlid), thromboxane-A2-receptor antagonists and thromboxane- A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term "direct thrombin inhibitors" Factor IIa inhibitors), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin directly, the inhibition of the cleavage of fibrinogen to fibrin, activation of Factor XIIla, activation of platelets, and feedback of thrombin to the coagulation cascade to generate more thrombin, occurs. Such direct inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban (Novastan), 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.

WO 01/81310 PCT[US01113810 -57- 0 O The term "fibrinolytic agents" (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots. Such agents include tissue plasminogen activator, anistreplase (Eminase), urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. 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.

The compounds of the present invention may be used in combination with any antihypertensive agent or cholesterol or lipid regulating agent, or concurrently in the treatment of restenosis, atherosclerosis or high blood pressure. Some examples of agents that are useful in 0 combination with a compound according to the invention in the treatment of high blood pressure include compounds of the following classes; beta-blockers, ACE inhibitors, calcium channel antagonists and alpha-receptor antagonists. Some examples of agents that are useful in combination with a compound according to the invention in the treatment of elevated cholesterol levels or disregulated lipid levels include compounds known to be HMGCoA reductase inhibitors, compounds of the fibrate class.

Other pharmaceutically active agents can be employed in combination with the compounds of the invention depending upon the disease being treated. For example, P-adrenergic agonist compound such as albuterol, terbutaline, formoterol, fenoterol, or prenaline; an anti-inflammatory corticosteroid compound such as beclomethasone, triamcinolone, flurisolide, or dexamethasone; an anticholinergics !0 compound such as ipratropium bromide; and an anti-inflammatory compound such as sodium cromoglycate or nedocromil sodium.

It is understood that the present invention includes combinations of compounds of the present invention with one or more of the aforementioned therapeutic class agents.

It is a further object of the invention to provide kits having a plurality of active ingredients (with or without carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of the invention.

It is another object of the invention to provide novel pharmaceutical compositions which is effective, in and of itself, for utilization in a beneficial combination therapy because it includes a plurality of active ingredients which may be utilized in accordance with the invention.

In another aspect, the present invention provides a method for treating a disease associated with factor Xa or tryptase activity in a patient in need of such treatment, said method including the steps of administering a therapeutically effective amount of the compound of formula I and administering a therapeutically effective amount of one of the aforementioned therapeutic class agents.

The invention also provides kits or single packages combining two or more active ingredients useful in treating a disease associated with factor Xa or tryptase activity. A kit may provide (alone or WO 01/81310 PCT[USOI/13810 -58in combination with a pharmaceutically acceptable diluent or carrier), the compound of formula I and one of the aforementioned therapeutic class agents (alone or in combination with diluent or carrier).

The present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of Formula I in association with a pharmaceutically acceptable carrier or coating.

In practice, compounds of the present invention may generally be administered parenterally, intravenously, subcutaneously intramuscularly, colonically, nasally, intraperitoneally, rectally or orally.

The products according to the invention may be presented in forms permitting administration by the most suitable route and the invention also relates to pharmaceutical compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.

The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed ini pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration.

WO 01/81310 PCT[USOI/13810 -59- Suitable compositions containing the compounds of the invention may be prepared by conventional means. For example, compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula 1.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.

Obviously, several unit dosage forms may be administered at about the same time. The dose employed >0 will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient In the adult, the doses are generally from about 0.0 1 to about 100, preferably about 0.0 1 to about 10, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to mg/kg body weight per day by oral administration, and from about 0.0.1 to about 50, preferably 0.01 to 10, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.

The products according to the invention may be administered as frequently as necessary in .0 order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of I to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.

The compounds of the present invention may also be formulated for use in conjunction with other therapeutic agents such as agents or in connection with the application of therapeutic techniques to address pharmacological conditions which may be ameliorated through the application of a compound of formula I, as described herein.

Compounds within the scope of the present invention exhibit marked pharmacological activities according to tests described in the literature and below which tests results are believed to correlate to pharmacological activity in humans and other mammals.

Enzyme Assays: The ability of the compounds in the present invention to act as inhibitors of factor Xa, thrombin, trypsin, tissue-plasmino gen activator urokinase-plasminogen activator (u-PA), plasmin and activated protein C is evaluated by determining the concentration of inhibitor which resulted in a 50% loss in enzyme activity (1C50) using purified enzymes.

WO 01/81310 PCTfUS01/13810 All enzyme assays are carried out at room temperature in 96-well microtiter plates using a final enzyme concentration of 1 nM. The concentrations of factor Xa and thrombin are determined by active site titration and the concentrations of all other enzymes are based on the protein concentration supplied by the manufacturer. Compounds according to the invention are dissolved in DMSO, diluted with their respective buffers and assayed at a maximal final DMSQ concentration of 1.25%.

Compound dilutions are added to wells containing buffer and enzyme and pre-equilibrated for between and 30 minutes. The enzyme reactions are initiated by the addition of substrate and the color developed from the hydrolysis of the peptide-p-nitroanilide substrates is monitored continuously for minutes at 405 nun on a Vmax niicroplate reader (Molecular Devices). Under these conditions, less than 10% of the substrate is utilized in all assays. The initial velocities measured are used to calculate the amount of inhibitor which resulted in a 50% reduction of the control velocity (1C50). The apparent Ki values are then determined according to the Cheng-Prusoff equation (1C50 Ki assuming competitive inhibition kinetics. Ki values for particular examples of compounds of the present invention with respect to Factor Xa, as well as Ki values for particular examples of compounds of the present invention with respect to tryptase, are set forth in the table below: EXAMPLE NAME Factor Xa Ki (nM) 8 3-[1 -(4-Pyridin-3-yl-benzoyl)- 1,2,3 ,6-tetrahydropyridin-4- yl]benzamidine ditrifuoroacetate.

l-[4-(5-Bromofuran-2-yl)-benzoyl]- 1,2,3,6- 34 tetrahydropyridin-4-yl}benzaznidine trifluoroacetate.

I1I 3- 1-[4-(5-Chlorothiophen-2-y}-benzoyl]- 1,2,3,6- 688 tetrahydropyridin-4.yllbenzaxnidine trifluoroacetate.

16 1-(4-Pyrimidin-2-ylbenzoyl)- 1,2,3,6-tetrahydropyridin-4- 63 yl-benzamidine ditrifluoroacetate.

3-[l -(4-Pyridin-2-ylbenzoyl)-piperidin-4-yl]benzamidine ditrifluoroacetate -Aminoisoquinolin-7-yl)piperidine-1.- 570 carbonyl]biphenyl-3-carboxylic acid amide trifluoroacetate 39 5- 1-Aminoisoquinolin-7-yl)-3 ,6-dihydro-2H-pyridine- 140 I-carbonyl]phenyl}-1H-pyridin-2-one trifluoroacetate________ 44 5- {4-[4-(4-Amino- lH-pyrrolo[3 ,2-c]pyridin-2-yl)piperidine- 990 -carbonyl]phenyl} H-pyridin-2-one trifluoroacetate EXAMPLE NAM Tryptase Ki (nM) 47 3-[l -(5-Phenylethynyl-pyridine-3-carbonyl)- 1,2,3,6- 183 __________tetrahydropyridin-4-yl]-benzamidine hydrochloride________ 49 3-[4-(5-Phenylethyl-pyridine-3-carbonyl)-piperazin- l-yl]- 1,070 ________benzamnidine di-hydrochioride I__ An additional in vitro assay may be used to evaluate the potency of compounds according to the invention in normal human plasma. The activated partial thromboplastin time is a plasma-based clotting assay that relies on the in situ generation of factor Xa, its assembly into the protbrombinase complex and the subsequent generation of thromnbin and fibrin which ultimately yields the formation of WO 01/81310 PCT/US01/13810 -61- S a clot as the assay endpoint. This assay is currently used clinically to monitor the ex vivo effects of the commonly used anticoagulant drug heparin as well as direct acting antithrombin agents undergoing S clinical evaluation. Therefore, activity in this in vitro assay is considered as a surrogate marker for in vivo anticoagulant activity.

Human Plasma Based Clotting Assay: Activated partial thromboplastin clotting times are determined in duplicate on a MLA Electra 800 instrument. A volume of 100 pl of citrated normal human pooled plasma (George King Biomedical) is added to a cuvette containing 100 pl of a compound according to the invention in Tris/NaCl buffer (pH and placed in the instrument. Following a 3 minute warming period the instrument automatically 0 adds 100 tl of activated cephaloplastin reagent (Actin, Dade) followed by 100 p.1 of 0.035 M CaCl2 to initiate the clotting reaction. Clot formation is determined spectrophotometrically and measured in seconds. Compound potency is quantitated as the concentration required to double a control clotting time measured with human plasma in the absence of the compound according to the invention.

Compounds according to the invention may also be evaluated for their in vivo antithrombotic efficacy in two well established animal experimental models of acute vascular thrombosis. A rabbit model ofjugular vein thrombosis and a rat model of carotid artery thrombosis are used to demonstrate the antithrombotic activity of these compounds in distinct animal model paradigms of human venous thrombosis and arterial thrombosis, respectively.

Experimental In Vivo Rabbit Venous Thrombosis Model: 0 This is a well characterized model of fibrin rich venous thrombosis that is validated in the literature and shown to be sensitive to several anticoagulant drugs including heparin (Antithrombotic Effect of Recombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) in Experimental Venous Thrombosis-a Comparison with Low Molecular Weight Heparin, J. Hoist, B. Lindblad, D.

Bergqvist, O. Nordfang, P.B. Ostergaard, J.G.L. Petersen, G. Nielsen and U. Hedner. Thrombosis and Haemostasis, 71, 214-219 (1994). The purpose of utilizing this model is to evaluate the ability of compounds to prevent the formation of venous thrombi (clots) in vivo generated at a site of injury and partial stasis in the jugular vein.

Male and female New Zealand white rabbits weighing 1.5-2 kg are anesthetized with 35 mg/kg of ketamine and 5 mg/kg xylazine in a volume of 1 mL/kg The right jugular vein is cannulated for infusion of anesthetic (ketamine/xylazine 17/2.5 mg/kg/hr at a rate of approximately 0.5 mL/hr) and administration of test substances. The right carotid artery is cannulated for recording arterial blood pressure and collecting blood samples. Body temperature is maintained at 39 0 C with a GAYMAR T-PUMP. The left external jugular vein is isolated and all side branches along an exposed 2-3 cm of vessel are tied off. The internal jugular vein is cannulated, just above the bifurcation of the common jugular, and the tip of the cannula is advanced just proximal to the common jugular vein. A 1 cm segment of the vein is isolated with non-traumatic WO 01/81310 PCT/US01/13810 -62vascular clamps and a relative stenosis is formed by tying a ligature around the vein with an 18G 1 needle just below the distal most clamp. This creates a region of reduced flow and partial stasis at the injury site. The isolated segment is gently rinsed with saline 2-3 times via the cannula in the internal jugular. Thereafter the isolated segment is filled with 0.5 mL of 0.5% polyoxyethylene ether for 5 5 minutes. W-1 is a detergent which disrupts the endothelial cell lining of the segment, thus providing a thrombogenic surface for initiating clot formation. After 5 minutes the W- is withdrawn from the O segment, and the segment is again gently rinsed with saline 2-3 times. The vascular clamps are then removed, restoring blood flow through this portion of the vessel. Clot formation is allowed to form and grow for 30 minutes after which the vein is cut just below the stenotic ligature and inspected for blood flow (the absence of blood flow is recorded as complete occlusion). The entire isolated segment of vein is then ligated and the formed clot is removed and weighed (wet weight). The effect of test agents on final clot weights is used as the primary end point. Animals are maintained for an additional thirty minutes to obtain a final pharmacodynamic measure of anticoagulation. Drug administration is initiated 15 minutes prior to vascular injury with W-1 and continued through the period of clot formation and maturation. Three blood samples (3 mL ea.) are obtained for evaluation ofhemostatic parameters: one just prior to administration of W-l; a second 30 minutes after removal of the vascular clamps and a third at the termination of the experiment. Antithrombotic efficacy is expressed as a reduction in the final clot weight in preparations treated with a compound according to the invention relative to vehicle treated control animals.

Experimental In Vivo Rat Arterial Thrombosis Model: The antithrombotic efficacy of factor Xa inhibitors against platelet-rich arterial thrombosis may be evaluated using a well characterized rat carotid artery FeCl2-induced thrombosis model (Superior Activity of a Thromboxane Receptor Antagonist as Compared with Aspirin in Rat Models of Arterial and Venous Thrombosis, W.A. Schumacher, C.L. Heran, T.E. Steinbacher, S. Youssefand M.L. Ogletree. Journal of Cardiovascular Pharmacology, 22, 526-533 (1993); Rat Model of Arterial Thrombosis Induced by Ferric Chloride, K.D. Kurtz, B.W. Main, and G.E. Sandusky. Thrombosis Research, 60, 269-280 (1990); The Effect of Thrombin Inhibition in a Rat Arterial Thrombosis Model, R.J. Broersma, L.W. Kutcher and E.F. Heminger. Thrombosis Research 64, 405-412 (1991). This model is widely used to evaluate the antithrombotic potential of a variety of agents including heparin and the direct acting thrombin inhibitors.

Sprague Dawley rats weighing 375-450 g are anesthetized with sodium pentobarbital mg/kg Upon reaching an acceptable level of anesthesia, the ventral surface of the neck is shaved and prepared for aseptic surgery. Electrocardiogram electrodes are connected and lead II is monitored throughout the experiment. The right femoral vein and artery are cannulated with PE-50 tubing for administration of a compound according to the invention and for obtaining blood samples and monitoring blood pressure, respectively. A midline incision is made in the ventral surface of the neck.

The trachea is exposed and intubated with PE-240 tubing to ensure airway patency. The right carotid WO 01/81310 PCTfUS01/13810 -63- 0 artery is isolated and two 4-0 silk sutures are placed around the vessel to facilitate instrumentation. An electromagnetic flow probe (0.95-1.0 mm lumen) is placed around the vessel to measure blood flow.

Distal to the probe a 4x4 mm strip of parafilm is placed under the vessel to isolate it from the surrounding muscle bed. After baseline flow measurements are made, a 2x5 mm strip of filter paper previously saturated in 35% FeCl2 is placed on top of the vessel downstream from the probe for ten minutes and then removed. The FeCI2 is thought to diffuse into the underlying segment of artery and cause deendothelialization resulting in acute thrombus formation. Following application of the FeCl2- CN soaked filter paper, blood pressure, carotid artery blood flow and heart rate are monitored for an C observation period of 60 minutes. Following occlusion of the vessel (defined as the attainment of zero S0 blood flow), or 60 minutes after filter paper application if patency is maintained, the artery is ligated S proximal and distal to the area of injury and the vessel is excised. The thrombus is removed and weighed immediately and recorded as the primary end point of the study.

Following surgical instrumentation a control blood sample (B1) is drawn. All blood samples are collected from the arterial catheter and mixed with sodium citrate to prevent clotting. After each blood sample, the catheter is flushed with 0.5 mL of 0.9% saline. A compound according to the invention is administered intravenously starting 5 minutes prior to FeCI2 application. The time between FeCl2 application and the time at which carotid blood flow reached zero is recorded as time to occlusion (TTO). For vessels that did not occlude within 60 minutes, TTO is assigned a value of minutes. Five minutes after application of FeCl2, a second blood sample is drawn After !0 minutes of FeCl2 exposure, the filter paper is removed from the vessel and the animal is monitored for the remainder of the experiment. Upon reaching zero blood flow blood a third blood sample is drawn (B3) and the clot is removed and weighed. Template bleeding time measurements are performed on the forelimb toe pads at the same time that blood samples are obtained. Coagulation profiles consisting of activated partial thromboplastin time (APTT) and prothrombin time (PT) are performed on all blood samples. In some instances a compound according to the invention may be administered orally. Rats are restrained manually using standard techniques and compounds are administered by intragastric gavage using a 18 gauge curved dosing needle (volume of 5 mL/kg). Fifteen minutes after intragastric dosing, the animal is anesthetized and instrumented as described previously. Experiments are then performed according to the protocol described above.

By way of example, Compound 184 shows KI values of 27.0 nM, 1.72 pM, and 2.71 pM, in the Factor Xa, trypsin, and thrombin assays, respectively. Compound 45 shows Ki values of 94.0 nM, 129 nM, and 477 nM, in the Factor Xa, trypsin, and thrombin assays, respectively. Compound 167 shows Ki values of 19.0 nM, 46 nM, and 1.228 M, in the Factor Xa, trypsin, and thrombin assays, respectively.

Tryptase Inhibition Activity: Tryptase inhibition activity is confirmed using either isolated human lung tryptase or recombinant human (3 tryptase expressed in yeast cells. Essentially equivalent results are obtained WO 01/81310 PCT/US01/13810 -64using isolated native enzyme or the expressed enzyme. The assay procedure employes a 96 well microplate (Costar 3590) using L-pyroglutamyl-L-prolyl-L-arginine-para-nitroanilide (S2366: Quadratech) as substrate (essentially as described by McEuen et. al. Biochem Pharm, 52, pp 331-340, 1996). Assays are performed at room temperature using 0.5mM substrate (2 x Ki) and the microplate is read on a microplate reader (Beckman Biomek Plate reader) at 405 nm wavelength.. To determine the compound concentration that inhibites half of the enzyme activity (ICso), the fraction of control activity (FCA) is plotted as a function of the inhibitor concentration The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof.

Claims

1. A compound of formula I: (I) wherein, Z is CH or N; is a single or double bond, provided that when Z is nitrogen atom, then is a single bond; R 3 is phenyl that is optionally substituted with one or two ring system substituents which may be the same or different, or pyridyl or thienyl that is optionally substituted by one or two ring system substituents which may be the same or different, and wherein, the pyridyl nitrogen atom is optionally oxidized to the corresponding N-oxide; and ring system substituents are selected from the group consisting of, O NH2 O NH, NH NMe, 0 NH 2 0 NH 2 NH 2 NMe 2 O NH2 O2N N NI- S N/ N N F bN"0 SNH NH 0 NH2 0 NH2 N N 0 NH 2 0 NH 2 NMe 2 s- NH 2 0 NH=0 NH, 00 N2 0 NH2 0 2 N O1e I ,N N In N2 NON N F N N F N ""N I-lS. INJ/ F OMe 67 1 Ny N 00 Me N, N, 0 N%' K)'e -1NMe 2

2--ja ON' OMe N NH, OMe N or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof. C1 2. The compound according to claim I wherein Z is CH.

3. The compound according to claim 1 wherein Z is N.

4. The compound according to claim 2 wherein Zis CH, The compound according to claim 4 wherein is a double bond.

6. The compound according to claim I wherein is a single bond.

7. The compound according to claim 3 wherein Z is N,

8. The compound according to claim 1, which is selected from the group consisting of NE NH NH 2 NH 2 CN)N 0 R 3 and 0 R wherein R 3 is selected from the group consisting of, 2007202110 08 Jun 2007 Zfl\ 0 0 z I. c>n 0-Z 0 Z 'D 0 (D 0 0 0 z 2007202110 08 Jun 2007 0 z z z 0'U 0 0 00 SOMe F OMeF s s/ I S. I N IN N ~OMeF %N -NOMe N N IN N IN N N. N IN N N a /10 Br N Cl 1/ NY NMe 2 -NH 2 00 FN N OMe OMe N N0 anndN N OMe.

9. The compound according to claim I selected from the group consisting of 3- {I 1,6-dihydropyridine-3-yl)-benzoyl]-1I,2,3,6-tetrahydropyridin-4 yll}benzamidine; 12 CN1 3-f{ 1-Oxypyridin-2-yl)-benzoyl]- 1,2,3,6-tetrahydropyridin-4 yl }benzamidine; 3- 1 -Oxypyridin-4-yl)-benzoyl]- 1,2,3,6-tetrahydropyridin-4-yl 4benzamidine; 00 3- f 1- [4-(6-Oxo- I ,6-dih ydropyridine-3 -yI)-benzoyl] -piperidi n-4-y 4 benza mid ine; 3- (1I-[4-(l1 -Oxypyridin-4-yl)-benzoyl]-piperi'din-4-yl 4 benzamidine; 3- 1-[4-(l1 -Oxypyridin-2-yl)-benzoyl]-piperidin-4-yl 4 benzamidine; CN1 1-(4-Pyridine-2-yl-benzoyl)-1 ,2,3,6-tetrahydropyridin-4-yI]benzamidine; 3- I -(4-Pyridin-3-yl-benzoyl)- I ,2,3,6-tetrahydropyridin-4-yI]benzamidineI 341 -(4-Pyridin-4-yl-benzoyl)- I ,2,3,6-tetrahydropyridin-4-yI]benzamidine; 3-f -[4-(5-Bromofuran-2-yI)-benzoyl]- 1,2,3,6-tetrahydropyridin-4-y 4benzamidine; 3 1- -Chi orothi ophen-2-yi)-benzoyl]j- 1, 2,3,6-tetrah ydropyri di n-4-yl benzamnidine; 3-f{ 1-(4-Thiophen-2-yI-benzoyl)- 1,2,3,6-tetrahydropyridin-4-yI }benzamidine; 3- (1-[3-(5-Chlorothiophen-2-yI)-acryloyl)- 1,2,3,6-tetrahydropyridin-4-y 4benzamidine; {2-[(2-Dimethylaminoethyl)methylamino]pyrimidin-4-yl 4benzoyl)- 1,2,3,6-tetrahydropyridin-4- yI }benzamidine; 1- 4-[2-(2-Dimethylaminoethyl)-6-oxo- 1,6-dihydropyridin-3-yI]benzoyl 4-1 ,2,3,6-tetrahydropyridin-4- yl)benzamidine; 3 -[1I yri midi n-2-ylbenzoyl)- 1 ,2,3,6-tetrahydropyri di n-4-y -benzami dine; I-(4-Pyrazin-2-ylbenzoyl)- 1,2,3,6-tetrahydropyridin-4-yI]-benzamidine; 3 -l -SulIfamoyl bi phenyl -4-carbonyl)- 1, 2,3,6-tetrahydrop yri d in-4-y -benzami 1dine; 73 -Sulfamoylbiphenyl-4-carbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzami dine; 3- {3 11-[4-(6-Methoxypyridazin-3-yl)benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yI]-benzamidine; 00 3- 1 1,6 dihydropyridazin-3-yI)benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 3- (1 -[4-(2-Aminopyrimidin-5-yl)benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 3- 1 -[4-(6-Methoxypyridin-3-yl)benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzam-idinc; 1-(4-(Pyrimidin-5-ylbenzoyl)- 1 ,2,3,6-tetrahydropyridin-4-y1]-benzamidine; 3 [1-(4-Pyri di n-2-ylbenzoyl)-piperi din-4-yl]benzamidine; 3 [1-(4-Pyridi1n-3 -yl benzoyl)-piperi di n-4-yl]benzami dine; 1-(4-Pyridin-4-ylbenzoyl)-piperidin-4-yl]benzamidine; 3- f 1 -[4-(6-Methoxypyridin-3-yl)benzoyl]-piperidin-4-yl }benzamidine; 3- 1 -[4-(6-Methoxypyridazin-3-yl)benzoyl]-piperidin-4-yl Ibenzamidine; 3- I 1 ,6-dihydropyridazin-3-yl)benzoyl]-piperidin-4-yl }benzamidine; 3[ 1I -Phenyl ethyl -pyridine-3 -carbonyl)-piperi din-4-yl ]-benzami dine; 1-(5-Phenylethynyl-pyridine-3-carbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 1-(5-Phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzamidine; and 3- -Phenyl ethyl -pyri dine- 3-carbonyl)-piperazin- I -yl ]-benzami dine. The compound according to claim I selected from the group consisting of 3 1 -Phenyl ethyl -pyridi ne-3 -carbon yl)-piperi din-4-yl ]-benzami dine; 74 ;Z 3 1 -(5-Phenylethynyl-pyridine-3-carbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 00 3- 1I -Phenyl ethyn yl-pyridine-3 -carbonyl)-piperi din-4-yl] -benzami dine; 3- I-[4-(6-Methoxypyridin-3-yl)benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 3-[]I-(4-(Pyrimi din-5-ylbenzoyl)- 1 ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; 03- I-[4-(6-Methoxypyridazin-3-yl)benzoyl]-piperidin-4-yl benzamidine; 3- 1 -Oxypyridin-2-yl)-benzoyl]-piperidin-4-yl benzamidine; 1-(4-Pyridine-2-yl-benzoyl)- 1 ,2,3,6-tetrahydropyridin-4-yI]benzamidine; 1-(4-Pyridin-4-yI-benzoyl)- I ,2,3,6-tetrahydropyridin-4-yI]benzamidine; {2-[(2-Dimethylaminoethyl)methylamino]pyrimidin-4-y benzoyl)- I ,2,3,6-tetrahydropyridin-4- yl~benzamidine; and -Phenylethyl-pyridine-3-carbonyl)-piperazin- I -yl]-benzami dine.

11. The compound according to claim 1 selected from the group consisting of 3- (1 -Oxypyridin-4-yI)-benzoyl]- 1 ,2,3,6-tetrahydropyridin-4-yl }benzamidine; 3- 1-[4-(6-Oxo- 1 ,6-dihydropyridine-3-yl)-benzoyl]-piperidin-4-y benzamidine; 3- I -Oxypyridin-4-yI)-benzoyl]-piperidin-4-yl }benzamidine; 3- I-[4-(6-Oxo- 1 ,6-dihydropyridine-3-yl)-benzoyl]- 1,2,3,6-tetrahydropyridin-4-yl benzamidine; 3- f 1 1,6 dihydropyridazin-3-yl)benzoyl]- I ,2,3,6-tetrahydropyridin-4-yl]-benzamidine; and 3- 1-[4-(6-Oxo- 1 ,6-dihydropyridazin-3-yl)benzoyl]-piperidin-4-yl }benzamidine.