# Patent

## Title
Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition

## Abstract

The present invention provides novel urea mimics and analogues of Formula (I):




or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, W, and R6 are as defined herein. These compounds are selective inhibitors of the human P2Y1 receptor which can be used as medicaments.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims the priority benefit of U.S. Provisional Application No. 60/694,801, filed Jun. 27, 2005, which is expressly incorporated fully herein by reference.


FIELD OF THE INVENTION
The present invention provides novel urea mimics and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.
BACKGROUND OF THE INVENTION
Purinoreceptors bind to and are activated by a variety of both ribosylated (nucleotide) and non-ribosylated (nucleoside) purines. This distinction has been used to classify these receptors into two broad groups: the P1 receptors (A1, A2a, A2b, and A3), which bind to and are activated by the nucleoside adenosine, and the P2 receptors, which comprise a second, more diverse class of receptors which are activated by a wide variety of nucleotides including ATP, ADP, UTP, and UDP. The P2 receptors can be further subdivided into two distinct types of receptors; the ionotropic P2X receptors that mediate cation flux across cellular membranes in response to ATP and the metabotropic P2Y family of receptors which are G-protein coupled receptors. In humans, the P2Y family of receptors is generally considered to consist of seven distantly related members; P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, and P2Y13 (Boeynaems, J. M. et al. Drug Development Research 2001, 52, 187-9). In addition, an eighth receptor, P2Y14, has been considered by some to be a member of this class although it does not respond to ribosylated nucleotides and is activated by UDP-glucose (Abbracchio, M. P. et al. Trends Pharmacol. Sci. 2003, 24, 52-5).
Several studies have suggested that modulators of specific members of the P2Y family of receptors could have therapeutic potential for the treatment of a variety of disorders (for review, see Burnstock, G. and Williams, M. J. Pharm. Exp Ther. 2000, 295, 862-9), including diabetes, cancer, cystic fibrosis, and the treatment of ischemia-reperfusion injury (Abbracchio M. P., Burnstock G. Pharmacol. Ther. 1994, 64, 445-475). P2Y1 receptors, almost ubiquitous among human organs (Janssens R; Communi D.; Pirotton S. et al. Biochem. Biophys. Res. Comm. 1996, 221, 588-593) have been identified on microglia (Norenberg W. et al.; Br. J. Pharmacol. 1994, 111, 942-950) and on astrocytes (Salter M. W. and Hicks J. L. J. Neurosc. 1995, 15, 2961-2971). Extracellular ATP activates microglial and/or astrocytes via P2Y receptors and leads directly to the release of inflammatory mediators. Microglia and astrocytes are believed to play a role in the progression of Alzheimer's disease and other CNS inflammatory disorders such as stroke and multiple sclerosis.
Two members of the P2Y family, P2Y1 and P2Y12, are of particular interest as they have now both been shown to act as important receptors for ADP in platelets (Jin, J. et al. Proc. Natl. Acad. Sci. 1998, 95, 8070). ADP is a key activator of platelets and platelet activation is known to play a pivotal role in thrombus formation under conditions of high shear stress such as those found in the arterial circulation. In addition, more recent data has suggested that platelet activation may also play a role in mediating thrombus formation under lower shear stress such as that found in the venous circulation. ADP activates platelets by simultaneously interacting with both P2Y1 and P2Y12 to produce two separate intracellular signals which synergize together to produce complete platelet activation. (Jin, J. et al. J. Biol. Chem. 1998, 273, 2030-4). The first signal arises from ADP driven activation of the P2Y1 receptor and can most easily be tracked by measuring the transitory increase in intracellular free Ca+2. This signal appears to mediate the initial shape change reaction and to initiate the process of platelet activation. The second signal appears to be derived from ADP activation of the P2Y12 receptor and serves to consolidate the process and produce an irreversible platelet aggregate. Using three structurally related but distinct inhibitors of P2Y1 (A3P5P, A3P5PS, and A2P5P), Daniel, J. L. et al. (J. Biol. Chem. 1998, 273, 2024-9), Savi, P. et al. (FEBS Letters 1998, 422, 291-5), and Hechler, B. et al. (Br. J. Haematol. 1998, 103, 858-66) were the first to publish the observation that the inhibition of P2Y1 activity alone could block ADP-driven aggregation independently of the P2Y12 receptor. Although inhibition of platelet reactivity is often thought of as firm evidence of an anti-thrombotic activity, these antagonists lacked the necessary pharmacological properties for in vivo study. The first direct demonstration that inhibition of P2Y1 activity could lead to an anti-thrombotic effect in vivo was reported by Leon, C. et al. Circulation 2001, 103, 718-23, in a model of thromboplastin induced thromboembolism using both a P2Y1 knock-out mouse and the P2Y1 antagonist MRS-2179 (Baurand, A. and Gachet, C. Cardiovascular Drug Reviews 2003, 21, 67-76). These results were subsequently extended to include the inhibition of both venous and arterial thrombosis in the rat (Lenain, N. et al. J. Thromb. Haemost. 2003, 1, 1144-9) and the confirmation of the phenotype of the P2Y1 knock-out mouse in a second laboratory using an independently derived animal (Fabre, J-E. et al. Nature Medicine 1999, 5, 1199-1202). These studies highlighted the need for more potent and selective P2Y1 antagonists and recently, using the P2Y1 antagonist MRS-2500, Hechler, B, et al. J. Pharmacol Exp. Ther. 2006, 316, 556-563, succeeded in demonstrating strong antithrombotic activity for a selective P2Y1 antagonist in the mouse. Taken together, these data suggest that the discovery of novel P2Y1 antagonists with improved pharmaceutical characteristics could have significant utility in the treatment of a variety of thrombotic or thromboembolic disorders (see Gachet, C et al. Blood Cell, Molecules and Disease 2006, 36, 223-227 for a recent review).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel urea mimics and analogues, which are useful as selective inhibitors of the P2Y1 receptor including stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The present invention also provides processes and intermediates for making the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present invention also provides a method for modulation of platelet reactivity comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present invention also provides a method for treating thrombotic or thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
The present invention also provides the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
The present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of a thrombotic or thromboembolic or other disorders.
These and other features of the invention will be set forth in the expanded form as the disclosure continues.


DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In a first embodiment, the present invention provides, inter alia, a compound of Formula (I):




or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

ring A is C6-10 aryl substituted with 0-5 R1, or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 R1;
ring B is a 5- to 6-membered heteroaryl comprising: carbon atoms and 1-4 ring heteroatoms selected from N, NR11, N→O, S(O)p, and O, wherein said heteroaryl is substituted with 0-4 R7;
W is —NHCOCH═CH—, —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCON(Me)-, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2NH—, —NHSO2CH2—, —NHSO2CH═CH—, —NHNONHNHCO—, —CH2CONH—,




R1 is, independently at each occurrence, F, Cl, Br, I, CF3, —CF2CF3, OCF3, —OCF2CF2H, —OCF2CF3, SiMe3, —(CRfRf)r—ORC, SRC, CN, NO2, —(CRfRf)r—NR12R13, —(CRfRf)r—C(O)Rc, —(CRfRf)r—CO2Rc, —(CRfRf)r—C(O)NR12R13, —OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-13 carbocycle substituted with 0-5 Rb, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR11, O, and S(O)p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 Rb;
R6 is —(CH2)n-phenyl substituted with 0-3 R6a or —(CH2)n-pyridyl substituted with 0-3 R6a;
R6a is, independently at each occurrence, F, Cl, Br, I, —(CRfRf)r—ORc, SRc, CN, CF3, OCF3, —(CRfRf)r—NR12R13, —C(O)Rc, —(CRfRf)r—C(O)ORc, —(CRfRf)r—C(O)NR12R13, —Si(Me)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-C4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-10 carbocycle substituted with 0-2 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Re;
alternatively, when two R6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb;
R7 is, independently at each occurrence, F, Cl, Br, I, OCF3, CF3, ORc, SRc, CN, NO2, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CH2)r—C3-7 cycloalkyl substituted with 0-3 Rb, —(CH2)r—C3-7 phenyl substituted with 0-3 Rb, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR7b, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rb;
alternatively, two R7s on two adjacent carbon atoms form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 ring heteroatoms selected from O, N, NR7b, and S(O)p;
R7b is H, C1-4 alkyl, —C(O)(C1-4 alkyl), —C(O)phenyl, —C(O)benzyl, or benzyl;
R11 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-8 alkyl substituted with 0-2 Ra, —C(O)(CH2)n(C3-6 cycloalkyl), —C(O)(CH2)nphenyl, —C(O)O(C1-8 alkyl), —C(O)O(CH2)n(C3-6 cycloalkyl), —C(O)O(CH2)nphenyl, —C(O)O(CH2)2-4(C1-4 alkyl), —C(O)NH(C1-6 alkyl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)nphenyl, —(CRfRf)r—C3-7 cycloalkyl, —(CRfRf)r-phenyl, or —(CRfRf)r-5- to 6-membered heterocycle; wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 Rb, and said heteroaryl and heterocycle are substituted with 0-2 Rb and comprise: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p;
R12 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-6 alkyl, —C(O)(C1-6 alkyl), —C(O)(CH2)n(C6-10 aryl), —C(O)(CH2)n(5- to 10-membered heteroaryl), —C(O)O(C1-4 alkyl), —(CH2)nC(O)NH(C1-6 alkyl), —(CH2)nC(O)NH(C6-10 aryl), —(CH2)nC(O)NH(5- to 10-membered heteroaryl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)n(C6-10 aryl), —S(O)2(CH2)n(5- to 10-membered heteroaryl), —(CH2)n—(C6-10 aryl), or —(CH2)n-5- to 10-membered heteroaryl; wherein said alkyl, and aryl are substituted with 0-2 Rg; and said heteroaryl is substituted with 0-2 Rg and comprises: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p;
R13 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
alternatively, R12 and R13, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising: carbon atoms and 1-2 additional heteroatoms selected from N, NR11, O, and S(O)p;
R14 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)r-phenyl;
Ra is, independently at each occurrence, F, OCF3, CF3, ORc, SRc, CN, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rb is, independently at each occurrence, H, ═O, F, Cl, Br, I, —(CH2)r—ORc, SRc, CN, NO2, CF3, OCF3, —(CH2)r—NR12R13, —C(O)Rc, —(CH2)r—C(O)ORc, —(CH2)r—C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CH2)r-C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rc is, independently at each occurrence, H, —OP(O)(OEt)2, C1-8 alkyl substituted with 0-3 Re, C2-8 alkenyl substituted with 0-3 Re, C2-8 alkynyl substituted with 0-3 Re, —(CRfRf)r—C3-8 cycloalkyl substituted with 0-3 Re, —(CRfRf)r—C6-10 aryl substituted with 0-3 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substitutd with 0-3 Re;
Rd is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Re is, independently at each occurrence, H, ═O, —(CH2)r—ORf, F, Cl, Br, I, CN, NO2, —(CH2)r—NR12R13, —C(O)Rf, —(CH2)r—C(O)OR—, —NR14C(O)Rf, —(CH2)r—C(O)NR12R13, —SO2NR12R13, —NR14SO2NR12R13, —NR14SO2—C1-4 alkyl, —NR14SO2CF3, —NR14SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-8 alkyl substituted with 0-2 Rg, C2-8 alkenyl substituted with 0-2 Rg, C2-8 alkynyl substituted with 0-2 Rg, —(CH2)r—C3-8 cycloalkyl substituted with 0-2 Rg, —(CH2)r—C6-10 aryl substituted with 0-2 Rg, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rg;
alternatively, two Re groups, together with the atoms to which they are attached, form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NRf, O, and S(O)p, 0-1 carbonyl and 0-3 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 Rg;
Rf is, independently at each occurrence, H, F, C1-6 alkyl, or —(CH2)n-phenyl;
Rg is, independently at each occurrence, H, ═O, ORf, F, Cl, Br, I, CN, NO2, —NRfRf, —C(O)Rf, —C(O)ORf, —NRfC(O)Rf, —C(O)NRfRf, —SO2NRfRf, —NRfSO2NRfRf, —NRfSO2—C1-4 alkyl, —NRfSO2CF3, —NRfSO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
provided that when W is —NHCOCH2NH—, B is




then ring A is other than 4-Cl-pyrid-3-yl.

In a second embodiment, the present invention provides a compound of Formula (I), within the scope of the first embodiment wherein:
ring A is substituted with 0-4 R1 and selected from:




and ring B is




substituted with 0-3 R7.

In a third embodiment, the present invention provides a compound of Formula (I), within the scope of the second embodiment wherein: W is —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCON(Me)-, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2CH2—, —NHCONHNHCO—, —CH2CONH—,




In a fourth embodiment, the present invention provides a compound of Formula (I), within the scope of the third embodiment wherein:
R1 is, independently at each occurrence, Me, Pr, i-Pr, Bu, t-Bu, F, Cl, Br, OMe, CF3, OCF3, CN, NO2, —(CH2)r—ORc, —(CH2)r—NR12R13, —(CH2)r—CO2Rc, —(CH2)r—C(O)NR12R3, C1-4 alkyl substituted with 0-2 Ra, C2-4 alkenyl substituted with 0-2 Ra, C2-4 alkynyl substituted with 0-2 Ra, —(CH2)r-phenyl substituted with 0-3 Rb, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-2 additional heteroatoms selected from N, NH, O, and S(O)p.
In a fifth embodiment, the present invention provides a compound of Formula (I), within the scope of the fourth embodiment wherein:
R1 is, independently at each occurrence, Me, Pr, i-Pr, Bu, t-Bu, F, Cl, Br, OMe, CF3, OCF3, N(Me)2, —CH2N(Me)2, —CH2N(Et)2, NO2, —OCOMe, Ph, OPh, —CH2OBn, 4-F-Ph, 2-OMe-Ph, or 2-Me-thiazol-4-yl;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-2 additional heteroatoms selected from N, NH, O, and S(O)p.
In a sixth embodiment, the present invention provides a compound of Formula (I), within the scope of the fifth embodiment wherein:
ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF3-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-N(Me)2-Ph, 2-CH2N(Me)2-Ph, 4-CH2N(Et)2-Ph, 3-NO2-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH2OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF3)-Ph, 1-naphthyl, 2-naphthyl,




In a seventh embodiment, the present invention provides a compound of Formula (I), within the scope of the sixth embodiment wherein: R6 is 2-t-Bu-Ph, or 3-t-Bu-Ph.
In an eighth embodiment, the present invention provides a compound of Formula (I), within the scope of the first embodiment wherein:
ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF3-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-N(Me)2-Ph, 2-CH2N(Me)2-Ph, 4-CH2N(Et)2-Ph, 3-NO2-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH2OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF3)-Ph, 1-naphthyl, 2-naphthyl,




ring B is selected from:




W is —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCON(Me)-, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2CH2—, —NHCONHNHCO—, —CH2CONH—,




R6 is 2-t-Bu-Ph, or 3-t-Bu-Ph.
In a ninth embodiment, the present invention provides a compound selected from the exemplified examples of the present invention or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof.
In another embodiment, the present invention provides a compound of Formula (I), wherein: R6 is 2-t-Bu-Ph.
In another embodiment, the present invention provides a compound of Formula (I), wherein: W is




In another embodiment, the present invention provides a compound of Formula (I), wherein: W is




In a tenth embodiment, the present invention provides, inter alia, a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I):




or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

ring A is C6-10 aryl substituted with 0-5 R1, or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 R1;
ring B is phenylene substituted with 0-3 R7 or a 5- to 6-membered heteroaryl comprising: carbon atoms and 1-4 ring heteroatoms selected from N, NR11, N→O, S(O)p, and O, wherein said heteroaryl is substituted with 0-4 R7; provided that ring B is other than phenylene substituted with —C(O)ORc;
W is —NHCOCH═CH—, —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCON(Me)-, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2NH—, —NHSO2CH2—, —NHSO2CH═CH—, —NHCONHNHCO—, —CH2CONH—,




R1 is, independently at each occurrence, F, Cl, Br, I, CF3, —CF2CF3, OCF3, —OCF2CF2H, —OCF2CF3, SiMe3, —(CRfRf)r—ORc, SRc, CN, NO2, —(CRfRf)r—NR12R13, —(CRfRf)r—C(O)Rc, —(CRfRf)r—CO2Rc, —(CRfRf)r—C(O)NR12R13, —OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-13 carbocycle substituted with 0-5 Rb, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to-7-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR11, O, and S(O)p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 Rb;
R6 is —(CH2)n-phenyl substituted with 0-3 R6a or —(CH2)n-pyridyl substituted with 0-3 R6a;
R6a is, independently at each occurrence, F, Cl, Br, I, —(CRfRf)r—ORc, SRc, CN, CF3, OCF3, —(CRfRf)r—NR12R13, —C(O)Rc, —(CRfRf)r—C(O)ORc, —(CRfRf)r—C(O)NR12R13, —Si(Me)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-C4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-10 carbocycle substituted with 0-2 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Re;
alternatively, when two R6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb;
R7 is, independently at each occurrence, F, Cl, Br, I, OCF3, CF3, ORc, SRc, CN, NO2, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CH2)r—C3-7 cycloalkyl substituted with 0-3 Rb, —(CH2)r—C3-7 phenyl substituted with 0-3 Rb, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR7b, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rb;
alternatively, two R7s on two adjacent carbon atoms form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 ring heteroatoms selected from O, N, NR7b, and S(O)p;
R7b is H, C1-4 alkyl, —C(O)(C1-4 alkyl), —C(O)phenyl, —C(O)benzyl, or benzyl;
R11 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-8 alkyl substituted with 0-2 Ra, —C(O)(CH2)n(C3-6 cycloalkyl), —C(O)(CH2)nphenyl, —C(O)O(C1-8 alkyl), —C(O)O(CH2)n(C3-6 cycloalkyl), —C(O)O(CH2)nphenyl, —C(O)O(CH2)2-4(C1-4 alkyl), —C(O)NH(C1-6 alkyl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)nphenyl, —(CRfRf)r—C3-7 cycloalkyl, —(CRfRf)r-phenyl, or —(CRfRf)r-5- to 6-membered heterocycle; wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 Rb, and said heteroaryl and heterocycle are substituted with 0-2 Rb and comprise: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p;
R12 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-6 alkyl, —C(O)(C1-6 alkyl), —C(O)(CH2)n(C6-10 aryl), —C(O)(CH2)n(5- to 10-membered heteroaryl), —C(O)O(C1-4 alkyl), —(CH2)nC(O)NH(C1-6 alkyl), —(CH2)rC(O)NH(C6-10 aryl), —(CH2)nC(O)NH(5- to 10-membered heteroaryl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)n(C6-10 aryl), —S(O)2(CH2)n(5- to 10-membered heteroaryl), —(CH2)n—(C6-10 aryl), or —(CH2)n-5- to 10-membered heteroaryl; wherein said alkyl, and aryl are substituted with 0-2 Rg; and said heteroaryl is substituted with 0-2 Rg and comprises: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p;
R13 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
alternatively, R12 and R13, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising: carbon atoms and 1-2 additional heteroatoms selected from N, NR11, O, and S(O)p;
R14 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)r-phenyl;
Ra is, independently at each occurrence, F, OCF3, CF3, ORc, SRc, CN, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rb is, independently at each occurrence, H, ═O, F, Cl, Br, I, —(CH2)r—ORc, SRc, CN, NO2, CF3, OCF3, —(CH2)r—NR12R13, —C(O)Rc, —(CH2)r—C(O)ORc, —(CH2)r—C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rc is, independently at each occurrence, H, —OP(O)(OEt)2, C1-8 alkyl substituted with 0-3 Re, C2-8 alkenyl substituted with 0-3 Re, C2-8 alkynyl substituted with 0-3 Re, —(CRfRf)r—C3-8 cycloalkyl substituted with 0-3 Re, —(CRfRf)r—C6-10 aryl substituted with 0-3 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substitutd with 0-3 Re;
Rd is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10- membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Re is, independently at each occurrence, H, ═O, —(CH2)r—ORf, F, Cl, Br, I, CN, NO2, —(CH2)r—NR12R13, —C(O)Rf, —(CH2)r—C(O)ORf, —NR14C(O)Rf, —(CH2)r—C(O)NR12R13, —SO2NR12R13, —NR14SO2NR12R13, —NR14SO2—C1-4 alkyl, —NR14SO2CF3, —NR14SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-8 alkyl substituted with 0-2 Rg, C2-8 alkenyl substituted with 0-2 Rg, C2-8 alkynyl substituted with 0-2 Rg, —(CH2)r—C3-8 cycloalkyl substituted with 0-2 Rg, —(CH2)r—C6-10 aryl substituted with 0-2 Rg, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rg;
alternatively, two Re groups, together with the atoms to which they are attached, form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NRf, O, and S(O)p, 0-1 carbonyl and 0-3 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 Rg;
Rf is, independently at each occurrence, H, F, C1-6 alkyl, or —(CH2)n-phenyl;
Rg is, independently at each occurrence, H, ═O, ORf, F, Cl, Br, I, CN, NO2, —NRfRf, —C(O)Rf, —C(O)ORf, —NRfC(O)Rf, —C(O)NRfRf, —SO2NRfRf, —NRfSO2NRfRf, —NRfSO2—C1-4 alkyl, —NRfSO2CF3, —NRfSO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
provided that when W is —NHCOCH2NH—, B is




then ring A is other than 4-Cl-pyrid-3-yl.

In an eleventh embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), within the scope of the tenth embodiment wherein:
ring A is substituted with 0-4 R1 and selected from:




and

ring B is phenylene substituted with 0-3 R7 or pyridylene substituted with 0-3 R7; provided that ring B is other than phenylene substituted with —C(O)ORc.
In a twelfth embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), within the scope of the eleventh embodiment wherein:
ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF3-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-N(Me)2-Ph, 2-CH2N(Me)2-Ph, 4-CH2N(Et)2-Ph, 3-NO2-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH2OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF3)-Ph, 1-naphthyl, 2-naphthyl,




W is —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCON(Me)-, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2CH2—, —NHCONHNHCO—, —CH2CONH—,




R6 is 2-t-Bu-Ph, or 3-t-Bu-Ph.
In another embodiment, the present invention provides, inter alia, a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia):




or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

ring A is a C3-13 carbocycle carbocycle substituted with 0-5 R1, or a 5- to 12-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 R1;
ring B is phenylene substituted with 0-4 R7 or a 5- to 6-membered heteroaryl comprising: carbon atoms and 1-4 ring heteroatoms selected from N, NR11, N→O, S(O)p, and O, wherein said heteroaryl is substituted with 0-4 R7; provided that ring B is other than phenylene substituted with —C(O)ORc;
W is —NR17COCH═CR16—, —NR17CO—, —NR17CO2—, —NR17CO2CR16R17—, —NR17CONR17—, —NR17(CR16R17)t—, —NR17SO2—, —NR17SO2NR17—, —NR17SO2CR16R17—, —NR17SO2CH═CR16—, —NR17CONHNHCO—, —NR17COCR16R17CONR17—, —CR16R17CONR17—,




Y is O, S, NH, —OCR18R19—, —CH═CH—, or —CONH—;
R1 is, independently at each occurrence, ═O, F, Cl, Br, I, CF3, —CF2CF3, OCF3, —OCF2CF2H, —OCF2CF3, SiMe3, —(CRfRf)r—ORc, SRc, CN, NO2, —(CRfRf)r—NR12R13, —(CRfRf)r—C(O)Rc, —(CRfRf)r—CO2Rc, —(CRfRf)r—C(O)NR12R13, —C(O)NR14(CRfRf)tN12R13, —(CRfRf)r—OC(O)NR12R13, —(CRfRf)r—NR14C(O)NR12R13, —(CRfRf)r—NR14C(O)Rd, —(CRfRf)r—NR14C(O)ORh, —NR14(CRfRf)nC(O)Rd, —NR14CO(CRfRf)nORc, —(CH2)r—CR13(═NORc), —S(O)pNR12R13, —(CRfRf)r—NR14S(O)pNR12R13, —NR14SO2CF3, —NR14S(O)pRd, —S(O)2CF3, —S(O)Rd, —S(O)2Rd, —OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-13 carbocycle substituted with 0-5 Rb, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR11, O, and S(O)p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 Rb;
R6 is —(CRfRf)n-phenyl substituted with 0-3 R6a or —(CRfRf)n-pyridyl substituted with 0-3 R6a;
R6a is, independently at each occurrence, F, Cl, Br, I, —(CRfRf)r—ORc, SRc, CN, NO2, CF3, OCF3, —CF2CF3, —OCF2CF2H, —OCF2CF3, —(CRfRf)r—NR12R13, —C(O)Rc, —(CRfRf)r—C(O)ORc, —(CRfRf)r—C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, —Si(Me)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-C4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-10 carbocycle substituted with 0-2 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Re;
alternatively, when two R6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb;
R7 is, independently at each occurrence, F, Cl, Br, I, OCF3, CF3, ORc, SRc, CN, NO2, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-10 carbocycle substituted with 0-3 Rb, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR7b, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rb;
alternatively, two R7s on two adjacent carbon atoms form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 ring heteroatoms selected from O, N, NR7b, and S(O)p, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R7c;
R7b is H, C1-4 alkyl, —C(O)(C1-4 alkyl), —C(O)phenyl, —C(O)benzyl, or benzyl;
R7c is, independently at each occurrence, H, F, Cl, Br, I, OCF3, CF3, ORc, SRc, CN, NO2, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-4 alkyl, phenyl substituted with 0-3 Rb, or benzyl substituted with 0-3 Rb;
R11 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-8 alkyl substituted with 0-2 Ra, C2-4 alkenyl substituted with 0-1 Ra, C2-4 alkynyl substituted with 0-1 Ra, —C(O)(C1-6 alkyl), —C(O)(CH2)n(C3-6 cycloalkyl), —C(O)(CH2)n(C6-10 aryl), —C(O)(CH2)n(5- to 10-membered heteroaryl), —C(O)O(C1-8 alkyl), —C(O)O(CH2)n(C3-6 cycloalkyl), —C(O)O(CH2)n(C6-10 aryl), —C(O)O(CH2)n(5- to 10-membered heteroaryl), —C(O)O(CH2)2-4(C1-4 alkyl), —C(O)NH(C1-8 alkyl), —C(O)NH(CH2)n(C3-6 cycloalkyl), —C(O)NH(CH2)n(C6-10 aryl), —C(O)NH(CH2)n(5- to 10-membered heteroaryl), —S(O)2(C1-8 alkyl), —S(O)2(CH2)n(C3-6 cycloalkyl), —S(O)2(CH2)n(C6-10 aryl), —S(O)2(CH2)n(5- to 10-membered heteroaryl), —(CRfRf)r—C3-7 cycloalkyl, —(CRfRf)r-phenyl, or —(CRfRf)r-5- to 6-membered heterocycle; wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 Rb, and said heteroaryl and heterocycle are substituted with 0-2 Rb and comprise: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p;
R12 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-6 alkyl, —C(O)(C1-6 alkyl), —C(O)(CH2)n(C6-10 aryl), —C(O)(CH2)n(5- to 10-membered heteroaryl), —C(O)O(C1-4 alkyl), —C(O)OCH2(C6-10 aryl), —(CH2)nC(O)OCH2(5- to 10-membered heteroaryl), —(CH2)nOC(O)(C1-4 alkyl), —(CH2)nOC(O)(C6-10 aryl), —(CH2)nOC(O)(5- to 10-membered heteroaryl), —(CH2)nC(O)O(C1-4 alkyl), —(CH2)nC(O)O(C6-10 aryl), —(CH2)nC(O)O(5- to 10-membered heteroaryl), —(CH2)nC(O)NH(C1-6 alkyl), —(CH2)nC(O)NH(C6-10 aryl), —(CH2)nC(O)NH(5- to 10-membered heteroaryl), —(CH2)tOC(O)NH(C1-6 alkyl), —(CH2)tOC(O)NH(C6-10 aryl), —(CH2)tOC(O)NH(5- to 10-membered heteroaryl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)n(C6-10 aryl), —S(O)2(CH2)n(5- to 10-membered heteroaryl), —(CH2)n—(C6-10 aryl), or —(CH2)n-5- to 10-membered heteroaryl; wherein said alkyl, and aryl are substituted with 0-2 Rg; and said heteroaryl is substituted with 0-2 Rg and comprises: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p;
R13 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
alternatively, R12 and R13, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising: carbon atoms and 1-2 additional heteroatoms selected from N, NR11, O, and S(O)p;
R14 is, independently at each occurrence, H, C1-6 alkyl substituted with 0-2 R14a, C2-6 alkenyl substituted with 0-2 R14a, C2-6 alkynyl substituted with 0-2 R14a, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rg, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rg;
R14a is, independently at each occurrence, H, C1-4 alkyl, ORf, Cl, F, Br, I, ═O, CF3, CN, NO2, —C(O)Rf, —C(O)ORf, —C(O)NR12R13, or —S(O)pRf;
R16 is, independently at each occurrence, H, F, C1-6 alkyl substituted with 0-2 Ra, C2-6 alkenyl substituted with 0-2 Ra, C2-6 alkynyl substituted with 0-2 Ra, or —(CH2)r-phenyl substituted with 0-2 Rb;
R17 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
alternatively, R16 and R17 on the same carbon atom combine to form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl, and 0-3 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb;
R18 is, independently at each occurrence, H, F, or C1-6 alkyl;
R19 is, independently at each occurrence, H, OH, —C(O)ORf, or C1-6 alkyl;
Ra is, independently at each occurrence, F, OCF3, CF3, ORc, SRc, CN, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rb is, independently at each occurrence, H, ═O, F, Cl, Br, I, —(CH2)r—ORc, SRc, CN, NO2, CF3, OCF3, —(CH2)r—NR12R13, —C(O)Rc, —(CH2)r—C(O)ORc, —(CH2)r—C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rc is, independently at each occurrence, H, —OP(O)(OEt)2, C1-8 alkyl substituted with 0-3 Re, C2-8 alkenyl substituted with 0-3 Re, C2-8 alkynyl substituted with 0-3 Re, —(CRfRf)r—C3-8 cycloalkyl substituted with 0-3 Re, —(CRfRf)r—C6-10 aryl substituted with 0-3 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substitutd with 0-3 Re;
Rd is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-3 Re, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Re is, independently at each occurrence, H, ═O, —(CH2)r—ORf, F, Cl, Br, I, CN, NO2, —(CH2)r—NR12R13, —C(O)Rf, —(CH2)r—C(O)ORf, —NR14C(O)Rf, —(CH2)r—C(O)NR12R13, —SO2NR12R13, —NR14SO2NR12R13, —NR14SO2—C1-4 alkyl, —NR14SO2CF3, —NR14SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-8 alkyl substituted with 0-2 Rg, C2-8 alkenyl substituted with 0-2 Rg, C2-8 alkynyl substituted with 0-2 Rg, —(CH2)r—C3-8 cycloalkyl substituted with 0-2 Rg, —(CH2)r—C6-10 aryl substituted with 0-2 Rg, or —(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rg;
alternatively, two Re groups, together with the atoms to which they are attached, form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NRf, O, and S(O)p, 0-1 carbonyl and 0-3 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 Rg;
Rf is, independently at each occurrence, H, F, C1-6 alkyl, or —(CH2)n-phenyl;
Rg is, independently at each occurrence, H, ═O, ORf, F, Cl, Br, I, CN, NO2, —NRfRf, —C(O)Rf, —C(O)ORf, —NRfC(O)Rf, —C(O)NRfRf, —SO2NRfRf, —NRfSO2NRfRf, —NRfSO2—C1-4 alkyl, —NRfSO2CF3, —NRfSO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
Rh is, independently at each occurrence, C1-6 alkyl substituted with 0-2 Rg, or —(CH2)n-phenyl substituted with 0-2 Rg;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and
t, at each occurrence, is selected from 1, 2, 3, and 4;
provided that when W is —NHCOCH2NH—, B is




then ring A is other than 4-Cl-pyrid-3-yl.

In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically-effective amount of a compound of Formula (Ia), wherein: W is —NHCOCH═CH—, —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCON(Me)-, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2CH2—, —NHSO2CH═CH—,




In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia), wherein: Y is O, S, or NH.
In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia), wherein: ring A is substituted with 0-5 R1 and selected from: phenyl, naphthyl, pyridinyl, thienyl, thiadiazolyl, pyrimidinyl, faranyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, benzothiazolyl, indolyl, benzimidazolyl, benzopyranyl, and dihydroindolyl.
In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia), wherein: ring A is substituted with 0-5 R1 and selected from:




In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), wherein: ring B is substituted with 0-3 R7 and selected from:




In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia), wherein:
R1 is, independently at each occurrence, F, Cl, Br, I, CF3, —CF2CF3, OCF3, —OCF2CF2H, —OCF2CF3, SiMe3, —(CRfRf)r—ORc, SRc, CN, NO2, —(CRfRf)r—NR12R13, —(CRfRf)r—C(O)Rc, —(CRfRf)r—CO2Rc, —(CRfRf)r—C(O)NR12R13, —OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-13 carbocycle substituted with 0-5 Rb, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-5 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR11, O, and S(O)p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 Rb.
In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia), wherein:
R6 is —(CH2)n-phenyl substituted with 0-3 R6a or —(CH2)n-pyridyl substituted with 0-3 R6a; and
R6a is, independently at each occurrence, F, Cl, Br, I, —(CRfRf)r—ORc, SRc, CN, CF3, OCF3, —CF2CF3, —OCF2CF2H, —OCF2CF3, —NR12R13, —C(O)Rc, —Si(Me)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-C4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CRfRf)r—C3-10 carbocycle substituted with 0-2 Re, or —(CRfRf)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Re;
alternatively, when two R6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb.
In another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (Ia), wherein: R11 is, independently at each occurrence, H, C1-8 alkyl substituted with 0-2 Ra, —C(O)(CH2)n(C3-6 cycloalkyl), —C(O)(CH2)nphenyl, —C(O)O(C1-8 alkyl), —C(O)O(CH2)n(C3-6 cycloalkyl), —C(O)O(CH2)nphenyl, —C(O)O(CH2)2-4(C1-4 alkyl), —C(O)NH(C1-6 alkyl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)nphenyl, —(CRfRf)r—C3-7 cycloalkyl, —(CRfRf)r-phenyl, or —(CRfRf)r-5- to 6-membered heterocycle; wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 Rb, and said heteroaryl and heterocycle are substituted with 0-2 Rb and comprise: carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
In another embodiment, the present invention provides a novel process for making a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
In another embodiment, the present invention provides a novel intermediate for making a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
In another embodiment, the present invention provides a pharmaceutical composition further comprising at least one additional therapeutic agent selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischemic preconditioning and/or myocardial stunning, or a combination thereof.
In another embodiment, the present invention provides a pharmaceutical composition wherein the additional therapeutic agent(s) is an antihypertensive agent selected from ACE inhibitors, AT-1 receptor antagonists, beta-adrenergic receptor antagonists, ETA receptor antagonists, dual ETA/AT-1 receptor antagonists, and vasopeptidase inhibitors, an antiarrythmic agent selected from IKur inhibitors, an anticoagulants selected from thrombin inhibitors, antithrombin-III activators, heparin co-factor II activators, factor VIIa inhibitors, factor Xa inhibitors, factor XIa inhibitors and kallikrein inhibitors, or antiplatelet agents selected from GPIIb/IIIa blockers, protease activated receptor (PAR-1) antagonists, phosphodiesterase-III inhibitors, other P2Y1 antagonists, P2Y12 antagonists, thromboxane receptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or a combination thereof.
In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from an anti-arrhythmic agent, an anti-hypertensive agent, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, a potassium channel blocker, a cholesterol/lipid lowering agent, or a combination thereof.
In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase, or a combination thereof.
In a preferred embodiment, the present invention provides pharmaceutical composition, wherein the additional therapeutic agent(s) are an anti-platelet agent or a combination thereof.
In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent is the anti-platelet agent selected from clopidogrel and aspirin, or a combination thereof.
In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent is the anti-platelet agent clopidogrel.
In another embodiment, the present invention provides a method for modulation of platelet reactivity comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
In another embodiment, the present invention provides a method for treating thrombotic or thromboembolic disorders comprising: administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
In another embodiment, the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
In another embodiment, the thromboembolic disorder is selected from the group consisting of unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
In another embodiment, the present invention provides a method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug form thereof in an amount effective to treat a thromboembolic disorder.
In another embodiment, the present invention provides a method, comprising: administering a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof in an amount effective to treat a thrombotic or thromboembolic disorder.
In another embodiment, the present invention provides a compound of the present invention for use in therapy.
In another embodiment, the present invention provides a compound of the present invention for use in therapy for treating a thrombotic and thromboembolic disorder.
In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a thrombotic or thromboembolic disorder.
In another embodiment, the present invention provides a novel article of manufacture, comprising: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thrombotic or thromboembolic disorder.
In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
In another embodiment, the present invention provides a novel article of manufacture, comprising: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention; and (c) a package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a thrombotic or thromboembolic disorder.
In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
Definitions
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials or optically active catalysts. Geometric isomers of double bonds such as olefins and C═N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. When no specific mention is made of the configuration (cis, trans or R or S) of a compound (or of an asymmetric carbon), then any one of the isomers or a mixture of more than one isomer is intended. The processes for preparation can use racemates, enantiomers, or diastereomers as starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatography or fractional crystallization. Compounds of the present invention, and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention. The inventive compounds may be in the free or hydrate form.
Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole. Preferably, the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.
The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbon atom of the carbonyl group or one carbon atom of the double bond be part of (i.e., within) the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).
In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative. In cases wherein there are quarternary carbon atoms on compounds of the present invention, these can be replaced by silicone atoms, provided they do not form Si—N or Si—O bond.
When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R1, then said group may optionally be substituted with up to three R1 groups and R1 at each occurrence is selected independently from the definition of R1. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C1-C10 alkyl” (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Additionally, for example, “C1-C6 alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. For example, “C2-C6 alkenyl” (or alkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3,pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain. For example, “C2-C6 alkynyl” (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. C3-7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
“Alkoxy” or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, “C1-C6 alkoxy” (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, “alkylthio” or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S—, ethyl-S—, and the like.
“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, “C1-C6 haloalkoxy”, is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like. Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S—, pentafluoroethyl-S—, and the like.
As used herein, “carbocycle” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and indanyl. When the term “carbocycle” is used, it is intended to include “aryl”.
As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclic group” is intended to mean a stable 9- or 10-membered carbocyclic ring system which contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5 or 6 membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
As used herein, the term “aryl”, “C6-C10 aryl” or “aromatic residue”, is intended to mean an aromatic moiety containing, if specified, the specified number of carbon atoms; for example phenyl or naphthyl. Unless otherwise specified, “aryl”, “C6-C10 aryl” or “aromatic residue” may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(═O)CH3, SCH3, S(═O)CH3, S(═O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
As used herein, the term “heterocycle” or “heterocyclic group” is intended to mean a stable 3, 4, 5, 6, or 7- membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, 13, or 14-membered bicyclic or tricyclic heterocyclic ring which is saturated, partially unsaturated or fully unsaturated, and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized to —NO—, —SO—, or —SO2—. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term “heterocycle” is used, it is intended to include heteroaryl.
Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Preferred 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.
Preferred 5- to 6- membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.
As used herein, the term “bicyclic heterocycle” or “bicyclic heterocyclic group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5 or 6-membered monocyclic aromatic ring comprising a 5 membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5 or 6 membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5 membered heterocycle, a 6 membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinoline, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxaline, and 1,2,3,4-tetrahydro-quinazoline.
Also included are fused ring and spiro compounds containing, for example, the above carbocycles or heterocycles.
Bridged rings are also included in the definition of carbocycle or heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
As used herein, the term “amine protecting group” means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Greene and Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (Fmoc); (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, the disclosure of which is hereby incorporated by reference.
Isotopically labeled compounds of the present invention, i.e., wherein one or more of the atoms described are replaced by an isotope of that atom (e.g., C replaced by 13C or by 14C; and isotopes of hydrogen include tritium and deuterium), are also provided herein. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% compound of the present invention (“substantially pure”), which is then used or formulated as described herein. Such “substantially pure” compounds are also contemplated herein as part of the present invention.
“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain a N-halo, S(O)2H, or S(O)H group.
In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

    
    
        a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol. 112, at pp. 309-396, edited by K. Widder, et. al. (Academic Press, 1985);
        b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H. Bundgaard, at pp. 113-191 (1991);
        c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992);
        d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and
        e) N. Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).
    
    


Compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield compounds of the present invention per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6 alkanoyloxy-C1-6alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C1-6alkoxycarbonyloxy-C1-6alkyl, e.g. methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl, and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
The term “solvate” means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes 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. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates and the like. Methods of solvation are generally known in the art.
As used herein, the term “patient” encompasses all mammalian species.
As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
“Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination with other active ingredients to inhibit P2Y1 or to treat the conditions or disorders listed herein. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect (in this case, inhibition of P2Y1) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antithrombotic effect, or some other beneficial effect of the combination compared with the individual components.
The term “pharmaceutical composition” means a composition comprising a compound of the invention in combination with at least one additional pharmaceutical carrier. A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 18th ed., 1990, which is incorporated herein by reference in its entirety.
Abbreviations as used herein, are defined as follows: “1×” for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL” for milliliter or milliliters, “μL” for microliter or microliters, “M” for molar, “mmol” for millimole or millimoles, “min” for minute or minutes, “h” for hour or hours, “rt” for room temperature, “atm” for atmosphere, “psi” for pounds per square inch, “conc.” for concentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight, “mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “LC-MS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “1H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, “tlc” for thin layer chromatography, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.













Me
methyl


Et
ethyl


MeOH
methanol


EtOH
ethanol


i-PrOH
isopropanol


Ph
phenyl


Bn
benzyl


Bu
butyl


iBu or i-Bu
isobutyl


Pr
propyl


iPr or i-Pr
isopropyl


t-Bu
tertiary butyl


AcOH
acetic acid


BOP
benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium



hexafluorophosphate


BINAP
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl


EtOAc
ethyl acetate


ADP
adenosine diphosphate


2MeS-ADP
2 methylthio adenosine diphosphate


cDNA
complimentary DNA


DCC
dicyclohexylcarbodiimide


DCE
1,2 dichloroethane


DCM
dichloromethane


DEAD
diethyl azodicarboxylate


DIC or DIPCDI
diisopropylcarbodiimide


DIEA
diethylpropyl amine


DMEM
Dulbecco's modified Eagle media


DME
dimethyl ether


DMF
dimethyl formamide


DMSO
dimethyl sulfoxide


EDC (or EDC.HCl)
3-ethyl-3′-


or EDCI (or EDCI.HCl)
(dimethylamino)propyl-carbodiimide hydrochloride (or 1-(3-


or EDAC
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)


EDTA
ethylenediaminetetraacetic acid


FBS
Fetal Bovine Serum


HEPES
4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid


HATU
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium



hexafluorophosphate


HOBt
1-hydroxybenzotriazole


LDA
lithium diisopropylamide


mCPBA or MCPBA
meta-chloroperbenzoic acid


OMs
mesylate, methanesulfoate


OTf
triflate, trifluoromethanesulfonate


OTs
tosylate, para-toluenesulfonate


D-PBS
Dulbecco's Phosphate Buffered Saline


Pd/C
palladium on carbon


SCX
Strong Cation Exchanger


THF
tetrahydrofuran


TFA
trifluoroacetic acid


TRIS
tris (hydroxymethyl) aminomethane









Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
A particularly useful compendium of synthetic methods which may be applicable to the preparation of compounds of the present invention may be found in Larock, R. C. Comprehensive Organic Transformations, VCH: New York, 1989. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.
Schemes 1-8 describe synthetic routes of making compounds of the invention. Scheme 1 describes the preparation of compounds of the invention from a key amine intermediate 1. Scheme 2 describes a preparation of carbamates and mono-N-alkyl ureas from the corresponding amine 1. Scheme 3 describes a preparation of sulfonamides and amides whereas Scheme 4 describe the synthesis of N-alkyl anilines and Scheme 5 describe the synthesis of semi-carbazides. Schemes 6,7 and 8 describe the preparation of the aniline intermediates 1.
Scheme 1 describes a one-step preparation of substituted cinnamides from the reaction of a key amine intermediate 1 and a cinnamoyl chloride (R=Aryl) in the presence of a base. A cinnamoic acid can also be converted to the corresponding cinnamoyl chloride using reagents such as oxalyl chloride or thionyl chloride or, alternatively, the cinnamoic acid can be used along with a key amine intermediate 1 and coupling reagents such as EDCI and HOBt.




Scheme 2 describes a preparation of carbamates 6 from the key amine intermediate 1 and a chloroformate derivative 5. Alternatively, N-alkyl urea 9 can be prepared by the addition of an amine 8 to a key isocyanate intermediate 7 which in turn can be derived from amine 1 using standard procedures using a phosgene equivalent.




Scheme 3 outlines a preparation of the sulfonamides 10. Anilines 1, prepared according to Schemes 4, 5 and 6 can be treated with a sulfonyl chloride to provide sulfonamide 10. Amides 10a are prepared in a similar manner by treating amine 1 with an acyl chloride 9a or, alternatively, with a carboxylic acid 9b using standard peptide coupling procedures.




Scheme 4 outlines the preparation of anilines 12 which can be obtained using standard reductive amination protocols and Scheme 5 describes the preparation of semicarbazides 15 which proceeds first via activation of the amine 1 with a reagent such as carbonyldiimidazole followed by the addition of an hydrazide reagent.








Scheme 6 outlines one possible preparation of amino derivatives 1, which proceeds by aromatic nucleophilic substitution followed by reduction. Nitroaryl derivatives or nitroheteroaryl derivatives 16, substituted in the ortho position with a halogen (such as chlorine, fluorine or bromine), are commercially available or can readily be prepared by one skilled in the art of organic synthesis. They can be reacted with nucleophiles such as substituted alcohols, substituted amines, or substituted thiols to provide the corresponding ether, amine or thioether, respectively. Typical reaction conditions involve the reaction of a nucleophile and a halo nitro derivative in an organic solvent such as THF, DMF, toluene, dioxane or n-butanol, in the presence of a base such as potassium carbonate, cesium carbonate, triethylamine, or DIEA. The reaction temperature is usually between room temperature and reflux condition. Sometimes microwave irradiation can be used to accelerate the rate of reaction. The preferred synthesis of diaryl ethers proceeds by an ortho chloro-nitroaryl derivative with a substituted phenol and cesium carbonate at 80° C. in DMF. Diaryl amines are preferably obtained by reacting an ortho chloro-nitroaryl derivative with a substituted aniline and triethylamine in butanol at 210° C. using microwave irradiation.
Following aromatic nucleophilic substitution, the resulting nitro derivative 18 can be reduced to the corresponding aniline. Typical conditions include hydrogenation in the presence of a metal catalyst such as palladium or platinum. Other conditions include treatment with reducing agents such as SnCl2 or Zinc powder with ammonium chloride.




Preparation of substituted pyridine amines such as 20, 21, 22, or 23 is shown in Scheme 7. The pyridine aniline 19 prepared as described in Scheme 6 can be brominated or chlorinated using agents such as N-bromosuccinimide or N-chlorosuccinimide in an organic solvent such as DMF. The resulting aromatic bromide can be converted to the corresponding nitrile by metal catalyzed cyanation. For example, reaction of the bromide 20 (X═Br) with copper (I) cyanide, tris-(dibenzylideneaceteone)-bispalladium, diphenylphosphine ferrocene and tetrabutylammonium cyanide affords the corresponding nitrile 21. The resulting nitrile can be hydrolyzed to the corresponding carboxylic acid using methods know in the art of organic synthesis such as treatment with aqueous sodium hydroxide. Conversion of the corresponding carboxylic acid to the methyl ester can be accomplished by treatment with trimethylsilyl diazomethane or with hydrochloric acid in methanol. Alternatively, the nitrile 21 can be converted to the corresponding ester 22 and amide 23 by acidic or basic hydrolysis.




Preparation of substituted pyridine amines such as 26, 27, 28 or 29 is shown in Scheme 8. The nitrochloro pyridine 24 can be prepared as described above for Scheme 6. The resulting aromatic bromide can be converted to the corresponding nitrile by metal catalyzed cyanation. For example, reaction of the bromide 26 (Z═Br) with copper (I) cyanide, tris-(dibenzylideneaceteone)-bispalladium, diphenylphosphine ferrocene and tetrabutylammonium cyanide affords the corresponding nitrile 27. The resulting nitrile can be hydrolyzed to the corresponding carboxylic acid using methods know in the art of organic synthesis such as treatment with aqueous sodium hydroxide. Conversion of the corresponding carboxylic acid to the methyl ester 28 can be accomplished by treatment with trimethylsilyl diazomethane or with hydrochloric acid in methanol. Alternatively, the nitrile 27 can be converted to the corresponding amide 29 by acidic or basic hydrolysis.




In the following experimental procedures, solution ratios express a volume relationship, unless stated otherwise. NMR chemical shifts (δ) are reported in parts per million.
Products were analyzed by reverse phase analytical HPLC carried out on a Shimadzu Analytical HPLC system running DiscoveryVP software using Method A: Phenominex Luna C18 column (4.6×50 mm) eluted at 4 mL/min with a 4 min gradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm), Method B: Phenominex Luna C18 column (4.6×50 mm) eluted at 4 mL/min with a 4 min gradient from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm), or Method C: Zorbax SB C18 column (4.6×75 mm) eluted at 2.5 mL/min with methanol/water with 0.2% H3PO4 as a gradient of 10% to 90% methanol over 8 min followed by holding at 90% methanol for 3 min (UV 220 nm). Purification of intermediates and final products was carried out via either normal or reverse phase chromatography. Normal phase chromatography was carried out on an ISCO CombiFlashTM System Sq16x using prepacked SiO2 cartridges eluted with gradients of hexanes and ethyl acetate. Reverse phase preparative HPLC was carried out using a Shimadzu Preparative HPLC system running DiscoveryVP software on a Shim-PackVP-ODS column (50 L×20 mm) at 20 mL/min, 6 min gradient 100% A to 100% B with the solvent system used for the analytical. LCMS were obtained on a Shimadzu HPLC system running DiscoveryVP software, coupled with a Waters Model PlatformLC mass spectrometer running MassLynx version 3.5 software using the same column and conditions as utilized for analytical described above.
EXAMPLES
The following Examples have been prepared, isolated and characterized using the methods disclosed herein. The following Examples demonstrate a partial scope of the invention and are not meant to limit the scope of the invention.
Example 1
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)cinnamamide
1a. 2-(2-tert-butylphenoxy)pyridin-3-amine: A solution of 2-chloro-3-nitropyridine (21.1 g, 133 mmol) in DMF (100 mL) was treated with 2-tert-butylphenol (23.5 mL, 153 mmol) and cesium carbonate (130 g, 398 mmol). The mixture was heated at 80° C. for 30 h. The reaction was cooled to rt and the mixture was poured into water (1 L) with stirring. The resulting yellow precipitate was filtered, washed with water, and recrystallized from ethanol to afford 2a (32.8 g, 90% yield) as beige crystals; HPLC purity: 92%, 3.66 min (Method A); 1H NMR (400 MHz, CD3OD) δ ppm 1.34 (s, 9 H), 6.93 (m, 1 H), 7.22 (m, 3 H), 7.47 (m, 1 H), 8.31 (dd, J=4.82, 1.75 Hz, 1 H), 8.46 (dd, J=7.89, 1.75 Hz, 1 H).
1b. 2-(2-tert-Butylphenoxy)pyridin-3-ylamine: 1a (7.2 g, 27 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (160 mL). Palladium on charcoal (10%, 360 mg, 0.33 mmol) was added and the mixture was stirred overnight under hydrogen atmosphere (40 Psi). The reaction mixture was filtered over Celite® and concentrated to afford 2b (7.2 g, 100% yield) as a white powder; HPLC purity: 100%, 2.87 min (Method A); [M+H]+=243.3.
Example 1
Cinnamoyl chloride (300 mg, 1.8 mmol) was added to a solution of 2-(2-tert-butylphenoxy)pyridin-3-amine (385 mg, 1.6 mmol) and 4-dimethylaminopyridine (20 mg) in pyridine (8.0 mL) at room temperature under argon. The mixture was stirred at rt for 16 h, and a saturated ammonium chloride solution was added (10 mL) along with dichloromethane (20 mL). The separated aqueous layer was extracted with dichloromethane (3×20 mL) and the combined organic layers were washed with brine, dried (anhydrous sodium sulfate), filtered and evaporated to yield an oily residue which was purified using flash-chromatography (dichloromethane with linear increments of triethylamine) to afford the title compound. Alternatively, Example 1 and related analogs could be prepared using standard peptide coupling protocols with (in this case) cinnamic acid, EDCI and HOBt in dichloromethane, albeit in lower yield. (M+H)=373. 1H nmr (400 MHz, CDCl3) δ ppm: 1.44 (s, 9H), 6.58 (d, J=15.4 Hz, 1H), 6.00 (dd, J=7.8, 1.4 Hz, 1H), 7.07 (dd, J=8.0, 5.0 Hz, 1H), 7.23 (m, 1H), 7.42 (m, 2H), 7.51 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (m, 2H), 7.81 (d, J=15.4 Hz, 1H), 7.90 (dd, J=5.0, 1.7 Hz, 1H), 8.02 (s, 1H), 8.92 (dd, J=7.8, 1.5 Hz, 1H).
Example 30
4-tert-butyl-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)benzenesulfonamide
To a solution of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (20 mg, 0.083 mmol) in pyridine (0.75 ml) was added 4-tert-butylbenzene-1-sulfonyl chloride (20 mg, 0.086 mmol). The reaction was allowed to set at rt overnight. Solvent was removed under vacuum. Purification by Prep. HPLC (C18 28 mm×100 mm, 20-100% solvent B, 10 min. gradient, 4 min. hold, 25 ml/min: solvent A=10% MeOH/Water+0.1% TFA, solvent B=90% MeOH/Water+0.1% TFA) provided Example 30 (16.3 mg, 0.037 mmol). (M+H)+=439.28.
Example 56
2-(2-tert-butylphenoxy)-N-(3-phenylpropyl)pyridin-3-amine
To a solution of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (92 mg, 0.38 mmol) and hydrocinnamaldehyde (76.5 mg, 0.57 mmol) in dichloromethane (2.0 mL) was added acetic acid (21.7 μL, 0.38 mmol) at rt. The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (121 mg, 0.57 mmol) was added. The mixture was stirred at rt for 3 h and a solution of potassium carbonate in water was added. The separated aqueous layer was extracted with dichloromethane (3×15 mL) and the combined organic layers were washed with brine, dried (anh. magnesium sulfate), filtered and evaporated. Purification by Prep. HPLC (C18 20 mm×100 mm, 20-100% solvent B, 10 min. gradient, 7 min. 20 ml/min: solvent A=10% MeOH/Water+0.05% ammonium acetate, solvent B=90% MeOH/Water+0.05% ammonium acetate) provided Example 56 (90 mg, 0.24 mmol). (M+H)+=361.
Example 58
p-tolyl 2-(2-tert-butylphenoxy)pyridin-3-ylcarbamate
An anhydrous THF solution (1 mL) containing the amine 1a (49 mg, 0.2 mmol) and p-tolyl chloroformate (37.4 mg, 0.22 mmol) was heated at 45° C. for 2 h. The reaction mixture was then purified by chromatography (15 g SiO2, eluted with hexane/EtOAc 0-100% in 20 min) to give Example 58 as a white solid (58 mg, 78%). MS (M+H)=377.2.
Example 60
1-benzoyl-4-(2-(2-tert-butylphenoxypyridin-3-yl)semicarbazide
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (212 mg, 0.88 mmol) and 1,1-carbonylimidazole (142 mg, 0.88 mmol) in THF (2.5 mL) was stirred at rt for 2 h. Benzoyl hydrazide (120 mg, 0.88 mmol) was then added and the mixture was stirred at rt for 16 h. A saturated solution of ammonium chloride (10 mL) and ethyl acetate (20 mL) was then added. The separated aqueous solution was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with brine, dried (anh. magnesium sulfate), filtered and evaporated. Purification by Prep. HPLC (C18 20 mm×100 mm, 20-100% solvent B, 10 min. gradient, 7 min. 20 ml/min: solvent A=10% MeOH/Water+0.05% ammonium acetate, solvent B=90% MeOH/Water+0.05% ammonium acetate) provided Example 60 (90 mg, 0.24 mmol). (M+H)+=405.
Example 61
3-(2-(2-tert-butylphenoxy)pyridin-3-yl)-1-methyl-1-p-tolylurea
An anhydrous THF solution (0.5 mL) containing 2-(2-tert-butylphenoxy)-3-isocyanatopyridine (28 mg, 0.1 mmol) (derived from amine 1a using standard procedures with phosgene equivalent) and N-methyl p-toluidine (18.2 mg, 0.15 mmol) was heated to 60° C. for 15 h. The eaction mixture was diluted with MeOH and purified by reverse-phase-HPLC to give Example 68 as a white solid (20 mg, 52%). MS (M+H)=390.2.
Example 69
N-(2-(3-tert-butylphenoxy)pyridin-3-yl)cinnamamide




69a. 2-(3-tert-butylphenoxy)pyridin-3-amine: 69a was prepared according to the procedure described above for 1a using 3-tert-butylphenol instead of 2-tert-butylphenol.
Example 69: Cinnamoyl chloride (246 mg, 1.48 mmol) was added to a solution of 2-(3-tert-butylphenoxy)pyridin-3-amine (325 mg, 135 mmol) in pyridine (3.3 mL) at room temperature under argon. The mixture was stirred at rt for 72 h, and a saturated ammonium chloride solution was added (10 mL) along with dichloromethane (20 mL). The separated aqueous layer was extracted with dichloromethane (3×20 mL) and the combined organic layers were washed with brine, dried (anhydrous sodium sulfate), filtered and evaporated to yield an oily residue which was purified using flash-chromatography (dichloromethane with linear increments of triethylamine) to afford Example 69. (M+H)=373.
Example 70
benzyl 2-(2-tert-butylphenoxy)pyridin-3-ylcarbamate
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (880 mg, 3.6 mmol), benzyl chloroformate (575 uL, 4.0 mmol) and Hunig's base (935 uL, 5.4 mmol) in dichloromethane (9.0 mL) was stirred at rt for 16 h. Saturated ammonium chloride was added and the separated aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried (anh. Magnesium sulfate), filtered and evaporated to yield a residue which was purified by reverse phase preparative HPLC. LC-MS m/z 377.1 [M+H]+.
Example 71
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-1H-benzo[d]imidazole-2-carboxamide
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (80 mg, 0.33 mmol), 1H-benzo[d]imidazole-2-carboxylic acid (54 mg, 0.33 mmol) and BOP (172 mg, 0.39 mmol) in DMF was stirred at rt for 3 days. LC-MS showed only a small amount of the desired product. The reaction was diluted with EtOAc (15 mL), washed with 1 N HCl solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated to give the crude product. Purification of the crude product by reverse phase preparative HPLC provided Example 71 (12 mg) as a yellow solid. LC-MS m/z 387.2 [M+H]+.
Example 72
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-1H-indole-3-carboxamide
Example 72 was prepared from 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) and 1H-indole-3-carboxylic acid using the procedure described for Example 70. LC-MS m/z 386.2 [M+H]+.
Example 73
2-(2-(2-tert-butylphenoxy)pyridin-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide
HATU (26 mg, 0.07 mmol) was added to 4-(trifluoromethoxy)aniline (12 mg, 0.07 mmol), 2-(2-(2-tert-butylphenoxy)pyridin-3-yl)acetic acid (10 mg, 0.035 mmol), and diisopropylethylamine (59 uL, 0.34 mmol) in DMF (0.5 mL) at rt and stirred overnight. The mixture was diluted with acetonitrile, filtered and purified directly by prep. HPLC to give Example 72 as a white solid. (M+H)+=445. 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=5.1 Hz, 1H); 7.82 (d, J=7.3 Hz, 1H); 7.60 (d, J=8.6 Hz, 2H); 7.41 (d, J=8.1 Hz, 1H); 7.21-7.05 (m, 5H); 6.80 (d, J=7.8 Hz, 1H); 3.90 (s, 2H); 1.31 (s, 9H).
Example 74
2-(2-(2-tert-butylphenoxy)pyridin-3-yl)-N-(4-tert-butylphenyl)acetamide
74a. 2-(2-tert-Butylphenoxy)-3-iodopyridine: To a solution of 2-(2-tert-butylphenoxy)-3-aminopyridine (3.30 g, 13.6 mmol) in conc. HCl:water (3:4, 70 mL) at 0° C. was added NaNO2 (1.04 g, 15.0 mmol). Gas evolution is immeadiately observed. The reaction was stirred at 0° C. for  ̃25 min. and then the reaction was slowly poured into a rt solution of KI (6.8, 40.8 mmol) in water (150 mL) to produce a dark liquid containing an amount of a black. After heating the reaction at 60° C. for 2 h, the reaction was cooled to rt and extracted with ethyl acetate (2×200 mL). The combined ethyl acetate extracts were then washed with saturated aqueous Na2SO3 (2×300 mL) and saturated aqueous Na2CO3 (1×300 mL). The ethyl acetate extracts were then dried over MgSO4, filtered and concentrated. Purification of the residue by flash chromatography—(110 g ISCO silica gel column, 0 to 5% EtOAc in hexane step gradient)—gave 74a (3.35 g) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (s, 9H); 6.74 (dd, J=7.47, 4.83 Hz, 1H); 6.93 (dd, J=7.91, 1.32 Hz, 1H); 7.12-7.25 (m, 2H); 7.45 (dd, J=7.91, 1.76 Hz, 1 H); 8.10 (dd, J=4.83, 1.76 Hz, 1H); 8.15 (dd, J=7.69, 1.54 Hz, 1H).
74b. 2-(2-(2-tert-butylphenoxy)pyridin-3-yl)malononitrile: Sodium hydride (34 mg of a 60% dispersion in oil, 0.85 mmol) was added to malononitrile (36 μL, 0.57 mmol) in DME (2.0 mL) at rt under argon. After 5 min palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) was added and followed by 74a (100 mg, 0.28 mmol). The reaction mixture was heated to reflux under argon for 2 h and then cooled to rt. The crude material was diluted with acetonitrile, filtered and purified directly by prep. HPLC to give 74b as a white solid. (M+H)+=292. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (d, J=4.8 Hz, 1H); 8.04 (d, J=7.6 Hz, 1H); 7.52 (d, J=7.1 Hz, 1H); 7.26 (m, 2H); 7.19 (m, 1H); 6.91 (d, J=7.6 Hz, 1H); 5.43 (s, 1H); 1.42 (s, 9H).
74c. 2-(2-(2-tert-butylphenoxy)pyridin-3-yl)acetic acid: 6M HCl (5.0 mL) was added to 74b (55 mg, 0.19 mmol) and heated to 100° C. overnight. The reaction was cooled and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated to give 74c. (M+H)+=286. 1H NMR (400 MHz, CD3OD) δ ppm 8:41 (dd, J=7.6, 1.5 Hz, 1H); 8.18 (dd, J=5.8, 1.7 Hz, 1H); 7.57 (m, 2H); 7.33 (m, 2H); 7.01 (m, 1H); 3.96 (s, 2H); 1.38 (s, 9H).
Example 74: HATU (25 mg, 0.07 mmol) was added to 4-tert-butylaniline (11 uL, 0.07 mmol), 74c (10 mg, 0.035 mmol), and diisopropylethylamine (58 uL, 0.34 mmol) in DMF (0.5 mL) at room temperature and stirred overnight. The mixture was diluted with acetonitrile, filtered and purified directly by prep. HPLC to give Example 74 as a white solid. (M+H)+=417. 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=5.1 Hz, 1H); 7.82 (d, J=7.3 Hz, 1H); 7.40 (m, 3H); 7.30 (m, 2H); 7.22-7.10 (m, 3H); 6.81 (d, J=7.8 Hz, 1H); 3.88 (s, 2H); 1.32 (s, 9H); 1.28 (s, 9H).
Additional examples were prepared in similar procedures as described above. Table 1 below summarizes representative examples of the compounds in the present invention.







TABLE 1













 











Ex
W
ring A
Chemical Name
MS data (M + H)














1




Ph
N-(2-(2-tert- butylphenoxy)pyridin-3- yl)cinnamamide
373


 


3




2-Me-Ph
(E)-N-(2-(2-tert- butylphenoxy)pyridin-3-yl)-3- o-tolylacrylamide
387


 


4




4-Br-Ph
(E)-3-(4-bromophenyl)-N-(2- (2-tert-butylphenoxy)pyridin- 3-yl)acrylamide
451, 453


 


5




4-Ph-Ph
(E)-3-(4-phenylphenyl)-N-(2- (2-tert-butylpbenoxy)pyridin- 3-yl)acrylamide
449


 


6




2-CH2N(Me)2-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3-(2- ((dimethylamino)methyl) phenyl)acrylamide
506


 


7




4-N(Me)2-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3-(4- (dimethylamino)phenyl)acrylamide
416


 


8




3-CF3-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3-(3- (trifluoromethyl)phenyl)acrylamide
441


 


9




3-OCF3-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3-(3- (trifluoromethoxy)phenyl)acrylamide
457


 


10




3-Me-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- m-tolylacrylamide
387


 


11




4-CH2N(Et)2-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3-(4- ((diethylamino)methyl)phenyl) acrylamide
458.3


 


12




2-Cl-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- (2-chlorophenyl)acrylamide
407, 409


 


13




2-Cl-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- (3-chlorophenyl)acrylamide
407,409


 


14




3-Br-Ph
(E)-3-(3-bromophenyl)-N-(2- (2-tert-butylphenoxy)pyridin- 3-yl)acrylamide
451,453


 


15




2-OMe-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- (2-methoxyphenyl)acrylamide
403


 


16




3-OMe-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- (3-methoxyphenyl)acrylamide
403


 


17




3-OPh-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- (3-phenoxyphenyl)acrylamide
465


 


18




4-OCF3-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3-(4- (trifluoromethoxy)phenyl)acrylamide
457


 


19




3-NO2-Ph
(E)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- (3-nitrophenyl)acrylamide
418


 


20




3,5-di(CF3)-Ph
(E)-3-(3,5-bis(trifluoro- methyl)phenyl)-N-(2-(2-tert- butylphenoxy)pyridin-3- yl)acrylamide
509


 


21




2-OCOMe-Ph
(E)-2-(3-(2-(2-tert- butylphenoxy)pyridin-3- ylamino)-3-oxoprop-1- enyl)phenyl acetate
431


 


22




3,5-di(OMe)-Ph
(E)-N-(2-(2-tert- butylphenoxy)pyridin-3-yl)-3- (3,5-dimethoxyphenyl)acrylamide
433


 


23
—NHCO—




N-(2-(2-tert- butylphenoxy)pyridin-3-yl)-6- chloro-2H-chromene-3-carboxamide
435, 437


 


24
—NHCO—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-4-phenyl- 1,2,3-thiadiazole-5-carboxamide
431


 


25




2-OMe-Ph
(Z)-N-(2-(2-tert- butylphenoxy)pyridin-3-yl)-3- (2-methoxyphenyl)acrylamide
403


 


26








(E)-N-(2-(2-tert- butylphenoxy)pyridin-3-yl)-3- phenyl-2-(thiophen-2-yl)acrylamide
455


 


27




4-CH2OBn-Ph
(E)-3-(4-(benzyloxymethyl) phenyl)-N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)acrylamide
493


 


28
—NHSO2CH2—
Ph
N-(2-(2-tert-butyl
397.2





phenoxy)pyridin-3-yl)(phenyl)





methanesulfonamide


29
—NHSO2—
Ph
N-(2-(2-tert-butyl-
383.2





phenoxy)pyridin-3-





yl)benzenesulfonamide


30
—NHSO2—
4-t-Bu-Ph
4-tert-butyl-N-(2-(2-tert-
439.3





butylphenoxy)pyridin-3-





yl)benzenesulfonamide


31
—NHSO2—
1-naphthyl
N-(2-(2-tert-butyl-
433.2





phenoxy)pyridin-3-yl)





naphthalene-1-sulfonamide


32
—NHSO2—
4-Pr-Ph
N-(2-(2-tert-butyl-
425.11





phenoxy)pyridin-3-yl)-4-





propylbenzenesulfonamide


33
—NHSO2—
4-CF3-Ph
N-(2-(2-tert-butyl-
451.04





phenoxy)pyridin-3-yl)-4-





(trifluoromethyl)benzenesulfonamide


34
—NHSO2CH2—
3-CF3-Ph
N-(2-(2-tert-butyl-
465.08





phenoxy)pyridin-3-yl)(3-





(trifluoromethyl)phenyl)





methanesulfonamide


35
—NHSO2CH2—
3,4-diCl-Ph
N-(2-(2-tert-butyl-
464.95





phenoxy)pyridin-3-yl)(3,4-





dichlorophenyl)methanesulfonamide


36
—NHSO2—
2-naphthyl
N-(2-(2-tert-butyl-
433.02





phenoxy)pyridin-3-





yl)naphthalene-2-sulfonamide


 


37




Ph
(E)-N-(2-(2-tert- butylphenoxy)pyridin-3-yl)-2- phenylethenesulfonamide
409.05


 


38
—NHSO2—
4-OCF3-Ph
N-(2-(2-tert-butyl-
466.98





phenoxy)pyridin-3-yl)-4-





(trifluoromethoxy)





benzenesulfonamide


39
—NHSO2—
3,5-diCl-Ph
N-(2-(2-tert-butyl-
450.91





phenoxy)pyridin-3-yl)-





3,5-dichlorobenzenesulfonamide


40
—NHSO2—
3-Br-Ph
3-bromo-N-(2-(2-tert-
460.91





butylphenoxy)pyridin-3-





yl)benzenesulfonamide


41
—NHSO2—
2,4-diCl-Ph
N-(2-(2-tert-butyl-
450.92





phenoxy)pyridin-3-yl)-





2,4-dichlorobenzenesulfonamide


42
—NHSO2—
3,5-di(CF3)-Ph
N-(2-(2-tert-butyl-
519.01





phenoxy)pyridin-3-yl)-





3,5-bis(trifluoromethyl)





benzenesulfonamide


43
—NHSO2—
3-(2-OMe-Ph)-OPh
N-(2-(2-tert-butyl-
505.06





phenoxy)pyridin-3-yl)-3-





(2-methoxyphenoxy)





benzenesulfonamide


44
—NHSO2—
3-Ph-Ph
N-(2-(2-tert-butyl-
459.04





phenoxy)pyridin-3-yl)-3-





phenylbenzenesulfonamide


 


45
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-5- fluoro-3-methylbenzo[b]thiophene- 2-sulfonamide
470.97


 


46
—NHSO2—
4-(4-F-Ph)-Ph
N-(2-(2-tert-butyl-
477.04





phenoxy)pyridin-3-yl)-4-(4-





fluorophenyl)benzenesulfonamide


 


47
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-4- methylthiophene-2-sulfonamide
402.99


 


48
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-5- methylthiophene-2-sulfonamide
403.00


 


49
—NHSO2CH2—
3,5-diCl-Ph
N-(2-(2-tert-butyl-
464.95





phenoxy)pyridin-3-yl)(3,5-





dichlorophenyl)methanesulfonamide


 


50
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl) benzo[b]thiophene-2-sulfonamide
438.97


 


51
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl) benzo[b]thiophene-3-sulfonamide
438.96


 


52
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4] dioxepine-7-sulfonamide
455.03


 


53
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-2,5- dichlorothiophene-3-sulfonamide
456.88


 


54
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-5- (2-methylthiazol-4- yl)thiophene-2-sulfonamide
485.98


 


55
—NHSO2—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-6- phenoxypyridine-3-sulfonamide
476.05


 


56
—NHCH2CH2CH2—
Ph
2-(2-tert-butylphenoxy)-N-(3-
361.1





phenylpropyl)pyridin-3-amine


57
—NHSO2—
Ph
N-benzyl-2-(2-tert-
333





butylphenoxy)pyridin-3-amine


58
—NHSO2—
4-Me-Ph
p-tolyl 2-(2-tert-
377.2





butylphenoxy)pyridin-3-





ylcarbamate


59
—NHCO2CH2—
3,5-diCl-Ph
3,5-dichlorobenzyl 2-(2-tert-
445.2, 447.1,





butylphenoxy)pyridin-3-
449.2, dichloride





ylcarbamate
isotopic pattern


60
—NHCONHNHCO—
Ph
1-benzoyl-4-(2-
405





(2-tert-butyl-





phenoxypyridin-3-





yl)semicarbazide


61
—NHCON(Me)-
4-Me-Ph
3-(2-(2-tert-butyl-
390.2





phenoxy)pyridin-3-yl)-1-





methyl-1-p-tolylurea


62
—NHCOCH2NH—
4-Me-Ph
N-(2-(2-tert-butyl-
390.22





phenoxy)pyridin-3-yl)-2-





p-tolylamino-





acetamide


63
—NHCOCH(Me)-
4-Cl-Ph
N-(2-(2-tert-butyl-
409.26





phenoxy)pyridin-3-yl)-2-





(4-chlorophenyl)propanamide


64
—NHCOCH2CH2—
Ph
N-(2-(2-tert-butyl-
375





phenoxy)pyridin-3-yl)-3-





phenylpropanamide


 


65




Ph
N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-3- phenylpropynamide
371


 


66
—NHCOCH2—
Ph
N-(2-(2-tert-butyl-
361





phenoxy)pyridin-3-yl)-2-





phenylacetamide


 


67
—NHSO2—




(R)-tert-butyl-2-((2-(2-tert- butylphenoxy)pyridin-3-yl) carbamoyl)indoline-1-carboxylate
489


 


68
—NHCOCH2CONH—
4-OCF3-Ph
N1-(2-(2-tert-butyl-
488





phenoxy)pyridin-3-yl)-N3-(4-





(trifluoromethoxy)phenyl)





malonamide


70
—NHCO2CH2—
Ph
benzyl 2-(2-tert-
377.1





butylphenoxy)pyridin-3-





ylcarbamate


 


71
—NHCO—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)- 1H-indole-3-carboxamide
386.2


 


72
—NHCO—




N-(2-(2-tert-butyl- phenoxy)pyridin-3-yl)-1H- benzo[d]imidazole-2-carboxamide
386.2


 


73
—CH2CONH—
4-OCF3-Ph
2-(2-(2-tert-butylphenoxy)
445





pyridin-3-yl)-N-(4-





(trifluoromethoxy) phenyl)acetamide


74
—CH2CONH—
4-t-Bu-Ph
2-(2-(2-tert-butyl-
417





phenoxy)pyridin-3-yl)-N-





(4-tert-butylphenyl)acetamide









Utility

The compounds of the present invention are anti-platelet agents and thus are useful to maintain the fluidity of blood. Additionally, compounds of the present invention are useful for the treatment or prophylaxis of platelet-associated disorders. As used herein, the term “platelet-associated disorder” refers to any disorder which may be prevented, partially alleviated, or cured by the administration of an anti-platelet agent.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function, for example, by inhibiting the aggregation, adhesion or granule content secretion of platelets.
The term “thrombosis”, as used herein, refers to formation or presence of a thrombus (pl. thrombi); clotting within a blood vessel which may cause ischemia or infarction of tissues supplied by the vessel. The term “embolism”, as used herein, refers to sudden blocking of an artery by a clot or foreign material which has been brought to its site of lodgment by the blood current. The term “thromboembolism”, as used herein, refers to obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel.
In general, a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation). The term “thromboembolic disorders (or conditions)” as used herein also includes arterial or venous cardiovascular or cerebovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.
Thus, the compounds of the present invention are useful in the treatment or prevention of various platelet associated disorders including: thrombotic or thromboembolic conditions; acute coronary syndromes (such as coronary artery disease, myocardial infarction (MI), unstable angina, and non-Q Wave MI); thromboembolic stroke (such as that resulting from atrial fibrillation or from ventricular mural thrombus (low ejection fraction)); venous thrombosis (including deep vein thrombosis); arterial thrombosis; cerebral thrombosis; pulmonary embolism; cerebral embolism; kidney embolisms; peripheral occlusive arterial disease (e.g., peripheral arterial disease, intermittent claudication, critical leg ischemia, prevention of amputation, prevention of cardiovascular morbidity such as MI, transient ischemic attack, stroke, or ischemic sudden death); thromboembolic consequenses of surgery, interventional cardiology or immobility; thromboembolic consequenses of medication (such as oral contraceptives, hormome replacement, and heparin); thrombotic consequenses of atherosclerotic vascular disease and atherosclerotic plaque rupture leading to tissue ischemia; prevention of atherosclerotic plaque formation; transplant atherosclerosis; thromboembolic complications of pregancy including fetal loss; thromboembolic consequences of thrombophilia (e.g., Factor V Leiden, and homocystinenimia); prothrombotic consequences and/or complications of cancer; coagulopathies (e.g., disseminated intravascular coagulation (DIC)); coagulation syndromes; vascular remodeling atherosclerosis, restenosis and systemic infection; prevention of metastesis and tumor implantation; diabetic complications including retinopathy, nephropathy and neuropathy; inflammation (e.g., thrombophlebitis); ischemia (such as that resulting from vascular occlusion, cerebral infarction, transient ischemic attack, stroke and related cerebral vascular diseases); Kasabach-Merritt syndrome; atrial fibrillation; ventricular enlargement (including dilated cardiac myopathy and heart failure); restenosis (e.g., following arterial injury-induced either endogenously or exogenously); thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis. The medical implants or devices include, but are not limited to: prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, and vessel grafts. The procedures include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis.
In addition to acting as anti-platelet agents, the compounds of the present invention may also find utility in a variety of other settings including as inhibitors of bone resorption such as encountered in various osteoporotic conditions, as inhibitors of insulin secretion in conditions of hyperinsulinemia, as vasoconstrictive agents such as those used in cases of septic or hypovolemic shock, as inhibitors of smooth muscle relaxation such for the treatment of incontinence or in other cases where inhibition of sympathetic nerve transmission would be of therapeutic benefit such as nociception or neuronal tissue regeneration. These and many other potential utilities for P2Y1 antagonists have been recently reviewed (Burnstock, G. and Williams, M. J. Pharm. Exp Ther. 2000, 295, 862-9) and are suggested therein.
Compounds of the present invention may additionally be useful as diagnostic agents and adjuncts. For example, the present compounds may be useful in maintaining the reactivity of fractionated whole blood containing platelets such as required for analytical and biological testing or transfusions. In addition, the compounds of the present invention may be useful for maintaining blood vessel patency in conjunction with vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, organ, tissue and cell implantation and transplantation. In addition, the compounds of the present invention may be useful for maintaining blood vessel patency in conjunction with interventional cardiology or vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, organ, tissue and cell implantation and transplantation.
P2Y1 Assays
A. Binding Assay
A membrane binding assay was used to identify inhibitors of [33P] 2MeS-ADP binding to cloned human P2Y1 receptors. The cDNA clone for human P2Y1 was obtained from Incyte Pharmaceuticals and its sequence confirmed by established techniques (for a compendium of techniques used see Ausubel, F. et al. Current Protocols in Molecular Biology 1995 John Wiley and Sons, NY, N.Y.). The essential coding sequences were subcloned into pCDNA 3.1 (Invitrogen) to produce a P2Y1 expression construct. This construct was then transfected into the human embryonic kidney cell line HEK-293 and stable transfectants selected in Genetcin® (G418 sulfate; Life Technologies). Several lines were screened for binding activity and one (HEK293 #49) selected for further characterization. Membranes were prepared by growing HEK293 #49 in 150 mm dishes in DMEM/10% FBS in the presence of 1 mg/ml G418 until cells were 80-90% confluent. Plates were then washed with cold (4° C.) D-PBS twice and cells harvested by scraping into 10 mL D-PBS. Cells were pelleted by centrifugation (1,000 g, 10 min, 4° C.) and the resulting pellet resuspended in Lysis Buffer (10 mM Tris (7.4), 5 mM MgCl2 containing Complete protease inhibitor cocktail (Roche Cat #1873580) as recommended by the manufacturer). The suspension was then homogenized in a Dounce homogenizer (10-15 strokes; B pestle, on ice) and the homogenate spun at 1,000 g, 4° C., 5 min to pellet large debris. The supernatant was centrifuged at 150,000 g, 4° C., for 1 hour and the resulting membrane pellet resuspended in 0.5-1 mL of Buffer B (15 mM HEPES (7.4), 145 mM NaCl, 0.1 mM MgCl2, 5 mM EDTA, 5 mM KCl) and stored at −70° C. until used.
Binding reactions were performed in WGA FlashPlates (PerkinElmer Life Sciences, Cat #SMP105A) in a volume of 200 μL containing  ̃45 fmol of P2Y1 receptor (5 μg of total protein), 0.5 nM [33P] 2MeS-ADP (PerkinElmer; 2,000 Ci/mmol), and various concentrations of the test compound (usually between 50 μM and 10 pM) in Buffer B containing 1% DMSO. Reactions were allowed to proceed to completion at room temperature for 1 hour and then the aqueous solution aspirated. Plates were sealed and the residual [33P] bound to the plate determined by scintillation counting. Dose-response curves (IC50) were fit by non-linear regression (XLFit, ID Business Solutions Ltd.) and binding constants (Ki) calculated using the Cheng-Prusoff relationship (Ki=IC50/(1+L/Kd) in which a Kd for 2MeS-ADP to the P2Y1 receptor was determined to be 1.4 nM.
In general, preferred compounds of the present invention, such as the particular compounds disclosed in the above examples, have been identified to exhibit Ki's of equal to or less than 10 μM in the P2Y1 binding assay, thereby demonstrating these preferred compounds of the present invention as especially effective modulators of P2Y1 activity. More preferred compounds have Ki's of equal to or less than 5 μM, preferably equal to or less than 1 μM, more preferably equal to or less than 0.5 μM.
The effectiveness of compounds of the present invention as antithrombotic agents can be determined using relevant in vivo thrombosis models, including In Vivo Electrically-induced Carotid Artery Thrombosis Models and In Vivo Rabbit Arterio-venous Shunt Thrombosis Models.
In Vivo Electrically-induced Carotid Artery Thrombosis (ECAT) Model:
The rabbit ECAT model, described by Wong et al. (J Pharmacol Exp Ther 2000, 295, 212-218), can be used in this study. Male New Zealand White rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics are supplemented as needed. An electromagnetic flow probe is placed on a segment of an isolated carotid artery to monitor blood flow. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the initiation of thrombosis. Thrombus formation is induced by electrical stimulation of the carotid artery for 3 min at 4 mA using an external stainless-steel bipolar electrode. Carotid blood flow is measured continuously over a 90-min period to monitor thrombus-induced occlusion. Total carotid blood flow over 90 min is calculated by trapezoidal rule. Average carotid flow over 90 min is then determined by converting total carotid blood flow over 90 min to percent of total control carotid blood flow, which would result if control blood flow had been maintained continuously for 90 min. The ED50 (dose that increased average carotid blood flow over 90 min to 50% of the control) of compounds are estimated by a nonlinear least square regression program using the Hill sigmoid Emax equation (DeltaGraph; SPSS Inc., Chicago, Ill.).
In Vivo Rabbit Arterio-venous (AV) Shunt Thrombosis Model:
The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al. J Pharmacol Exp Ther 2000, 292, 351-357), can be used in this study. Male New Zealand White rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics are supplemented as needed. The femoral artery, jugular vein and femoral vein are isolated and catheterized. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of an outer piece of tygon tubing (length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing (length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an 8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread induces the formation of a significant thrombus. Forty minutes later, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by a nonlinear least square regression program using the Hill sigmoid Emax equation (DeltaGraph; SPSS Inc., Chicago, Ill.).
The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These other agents include, but are not limited to, anticoagulant or coagulation inhibitory agents, other antiplatelet or platelet inhibitory agents, or thrombolytic or fibrinolytic agents.
By “administered in combination” or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
Examples of suitable anti-arrhythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class II agents (such as carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide, and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as IAch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in WO01/40231).
Examples of suitable antihypertensive agents for use in combination with the compounds of the present invention include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g. diltiazem, verapamil, nifedipine, amlodipine, and mybefradil); diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); angiotensin AT-I receptor antagonists (e.g., losartan, irbesartan, valsartan); ET-A receptor antagonists (e.g., sitaxsentan, atrsentan, and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET-A/AT-1 antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat, gemopatrilat, and nitrates); and β-blockers (e.g., propanolol, nadolo, or carvedilol).
Examples of other suitable anti-platelet agents for use in combination with the compounds of the present invention, include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as acetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl, ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen, phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, and pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) and piroxicam are preferred. Other suitable platelet inhibitory agents include glycoprotein IIb/IIIa blockers (e.g., abciximab, eptifibatide, tirofiban, integrelin), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g., SCH-530348, SCH-203099, SCH-529153, and SCH-205831), and pharmaceutically acceptable salts or prodrugs thereof.
Other examples of suitable anti-platelet agents for use in combination with the compounds of the present invention, with or without aspirin, include: ADP (adenosine diphosphate) receptor antagonists including P2Y12 antagonists and other P2Y1 antagonists. Preferred P2Y12 receptor antagonists, but are not limited to, clopidogrel, ticlopidine, prasugrel, and AZD-6140, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine and clopidogrel are also preferred compounds since they are known to be more gentle than aspirin on the gastro-intestinal tract in use. Clopidogrel is an even more preferred agent.
Examples of suitable anticoagulants for use in combination with the compounds of the present invention include warfarin and heparin (either unfractionated heparin such as enoxaparin and dalteparin or any commercially available low molecular weight heparin, for example LOVENOXTM), synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and argatroban, factor VIIa inhibitors, factor IXa inhibitors, factor Xa inhibitors (e.g., ArixtraTM, apixaban, rivaroxaban, LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO 03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, and inhibitors of activated TAFI and PAI-1 known in the art.
The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the secretion of platelet granule contents including serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, and those disclosed in WO 98/37075 and WO 02/044145, and 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.
The term thrombolytic (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, and XIa, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Examples of suitable calcium channel blockers (L-type or T-type) for use in combination with the compounds of the present invention include diltiazem, verapamil, nifedipine, amlodipine and mybefradil.
Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
Examples of suitable diruetics for use in combination with the compounds of the present invention include: chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, and spironolactone.
Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include sprionolactone and eplirinone.
Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; nicotonic acid; fenofibric acid derivatives (e.g., gemfibrozil, clofibrat, fenofibrate and benzafibrate); probucol; choesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g. metformin); glucosidase inhibitors (e.g. acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g. repaglinide); sulfonylureas (e.g., glimepiride, glyburide and glipizide); biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g. troglitazone, rosiglitazone, and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors.
Examples of suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.
Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protein tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2 inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and/or rofecoxib.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.
Examples of suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol.
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat, aP2 inhibitors (such as those disclosed in WO00/59506), and cannabinoid receptor CB1 antagonists (e.g., rimonabant, AVE-1625, SR-147778, and CP-945598).
Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate.
Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.
Examples of suitable anti-ulcer and gastroesophageal reflux disease agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.
Administration of the compounds of the present invention (i.e., a first therapeutic agent) in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent), preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. It is preferred that at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses. Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated. Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of platelet ADP receptor. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving platelet ADP receptor. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.
The compounds of the present invention may also be used in diagnostic assays involving platelet ADP receptor. For example, the presence of P2Y1 in an unknown sample could be determined by addition of the relevant radiolabled compound to the sample and measuring the extend of binding to the P2Y1 receptor.
The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic disorder (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat a thromboembolic disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
Dosage and Formulation
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 0.1 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of the present invention and about 0.1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 100 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 50 milligrams per dosage unit.
Where the compounds of the present invention are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of the present invention and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of the present invention and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
Where the compounds of the present invention are administered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of the present invention, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 50-80% when administered with a compound of the present invention.
Where two or more of the foregoing second therapeutic agents are administered with the compound of the present invention, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

## Claims

1. A compound of Formula (I):




or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring A is C6-10 aryl substituted with 0-5 R1;
ring B is





substituted with 0-3 R7;
W is —NHCOCH═CH—, —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2NH—, —N HSO2CH2—, —NHSO2CH═CH—, —NHCONHNHCO—, —CH2CONH—,




R1 is, independently at each occurrence, F, Cl, Br, I, CF3, —CF2CF3, OCF3, —OCF2CF2H, —OCF2CF3, SiMe3, —(CRfRf)r—ORc, SRc, CN, NO2, —(CRfRf)r—NR12R13, —(CRfRf)r—C(O)Rc, —(CRfRf)r—CO2Rc, —(CRfRf)r—C(O)NR12R13, —OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, or —(CRfRf)r—C3-13 carbocycle substituted with 0-5 Rb;
R6 is —(CH2)n-phenyl substituted with 0-3 R6a;
R6a is, independently at each occurrence, F, Cl, Br, I, —(CRfRf)r—ORc, SRc, CN, CF3, OCF3, —(CRfRf)r—NR12R13, —C(O)Rc,—(CRfRf)r—C(O)ORc, —(CRfRf)r—C(O)NR12R13, —Si(Me)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, or —(CRfRf)r—C3-10 carbocycle substituted with 0-2 Re;
R7 is, independently at each occurrence, F, Cl, Br, I, OCF3, CF3, ORc, SRc, CN, NO2, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —(CH2)r—C3-7 cycloalkyl substituted with 0-3 Rb, or —(CH2)r—C3-7 phenyl substituted with 0-3 Rb;
R12 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-6 alkyl, —C(O)(C1-6 alkyl), —C(O)(CH2)n(C6-10 aryl), —C(O)O(C1-4 alkyl), —(CH2)nC(O)NH(C1-6 alkyl), —(CH2)C(O)NH(C6-10 aryl), —S(O)2(C1-6 alkyl), —S(O)2(CH2)n(C6-10 aryl), or —(CH2)n—(C6-10 aryl);
R13 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
R14 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)r-phenyl;
Ra is, independently at each occurrence, F, OCF3, CF3, ORc, SRc, CN, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13—S(O)Rd, —S(O)2Rd, or —(CH2)r—C3-10 carbocycle substituted with 0-3 Re;
Rb is, independently at each occurrence, H, ═O, F, Cl, Br, I, —(CH2)r—ORc, SRc, CN, NO2, CF3, OCF3, —(CH2)r—NR12R13,—C(O)Rc, —(CH2)r—C(O)ORc, —(CH2)r—C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13—S(O)Rd, —S(O)2Rd, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, or —(CH2)r—C3-10 carbocycle substituted with 0-3 Re;
Rc is, independently at each occurrence, H, —OP(O)(OEt)2, C1-8 alkyl substituted with 0-3 Re, C2-8 alkenyl substituted with 0-3 Re, C2-8 alkynyl substituted with 0-3 Re, —(CRfRf)r—C3-8 cycloalkyl substituted with 0-3 Re, or —(CRfRf)r—C6-10 aryl substituted with 0-3 Re;
Rd is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, or —(CH2)r—C3-10 carbocycle substituted with 0-3 Re;
Re is, independently at each occurrence, H, ═O, —(CH2)r—Of, F, Cl, Br, I, CN, NO2, —(CH2)r—NR12R13, —C(O)Rf, —(CH2)r—C(O)ORf, —NR14C(O)Rf, —(CH2)r—C(O)NR12R13, —SO2NR12R13, —NR14SO2NR12R13, —NR14SO2—C1-4 alkyl, —NR14SO2CF3, —NR14SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-8 alkyl substituted with 0-2 Rg, C2-8 alkenyl substituted with 0-2 Rg, C2-8 alkynyl substituted with 0-2 Rg, —(CH2)r—C3-8 cycloalkyl substituted with 0-2 Rg, or —(CH2)r—C6-10 aryl substituted with 0-2 Rg;
Rf is, independently at each occurrence, H, F, C1-6 alkyl, or —(CH2)n-phenyl;
Rg is, independently at each occurrence, H, ═O, ORf, F, Cl, Br, I, CN, NO2, —NRfRf, —C(O)Rf, —C(O)ORf, —NRfC(O)Rf, —C(O)NRfRf, —SO2NRfRf, —NRfSO2NRfRf, —NRfSO2—C1-4 alkyl, —NRfSO2CF3, —NRfSO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, 2, 3, and 4.

2. A compound according to claim 1, wherein:
ring A is substituted with 0-4 R1 and selected from:

3. A compound according to claim 2, wherein:
W is —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2CH2—, —NHCONHNHCO—, —CH2CONH—,

4. A compound according to claim 3, wherein:
R1 is, independently at each occurrence, Me, Pr, i-Pr, Bu, t-Bu, F, Cl, Br, OMe, CF3, OCF3, CN, NO2, —(CH2)r—ORc, —(CH2)r—NR12R13, —(CH2)r—CO2Rc, —(CH2)r—C(O)NR12R13, C1-4 alkyl substituted with 0-2 Ra, C2-4 alkenyl substituted with 0-2 Ra, C2-4 alkynyl substituted with 0-2 Ra, or —(CH2)r-phenyl substituted with 0-3 Rb.

5. A compound according to claim 4, wherein:
R1 is, independently at each occurrence, Me, Pr, i-Pr, Bu, t-Bu, F, Cl, Br, OMe, CF3, OCF3, N(Me)2, —CH2N(Me)2, —CH2N(Et)2, NO2, —OCOMe, Ph, OPh, —CH2OBn, 4-F-Ph, or 2-OMe-Ph.

6. A compound according to claim 5, wherein:
ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF3-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-N (Me)2-Ph, 2-CH2N(Me)2-Ph, 4-CH2N(Et)2-Ph, 3-NO2-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH2OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF3)-Ph, 1-naphthyl, or 2-naphthyl.

7. A compound according to claim 6, wherein:
R6 is 2-t-Bu-Ph, or 3-t-Bu-Ph.

8. A compound according to claim 1, wherein:
ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF3-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-N (Me)2-Ph, 2-CH2N(Me)2-Ph, 4-CH2N(Et)2-Ph, 3-NO2-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH2OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF3)-Ph, 1-naphthyl, or 2-naphthyl;
ring B is selected from:




W is —NHCO—, —NHCO2—, —NHCO2CH2—, —NHCOCH2NH—, —NHCOCH(Me)-, NHCOCH2CH2—, —NHCOCH2CONH—, —NHCH2—, —NHCH2CH2CH2—, —NHSO2—, —NHSO2CH2—, —NHCONHNHCO—, —CH2CONH—,





and
R6 is 2-t-Bu-Ph, or 3-t-Bu-Ph.

9. A compound according to claim 1, wherein the compound is selected from the group consisting of:
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)cinnamamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-o-tolylacrylamide,
(E)-3-(4-bromophenyl)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)acrylamide,
(E)-3-(4-phenylphenyl)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(2-((dimethylamino)methyl)phenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(4-(dimethylamino)phenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3-(trifluoromethoxy)phenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-m-tolylacrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(4-((diethylamino)methyl)phenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(2-chlorophenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3-chlorophenyl)acrylamide,
(E)-3-(3-bromophenyl)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(2-methoxyphenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3-methoxyphenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3-phenoxyphenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(4-(trifluoromethoxy)phenyl)acrylamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3-nitrophenyl)acrylamide,
(E)-3-(3,5-bis(trifluoromethyl)phenyl)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)acrylamide,
(E)-2-(3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-3-oxoprop-1-enyl)phenyl acetate,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(3,5-dimethoxyphenyl)acrylamide,
(Z)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(2-methoxyphenyl)acrylamide,
(E)-3-(4-(benzyloxymethyl)phenyl)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)acrylamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)(phenyl)methanesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)benzenesulfonamide,
4-tert-butyl-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)naphthalene-1-sulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-propylbenzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)(3-(trifluoromethyl)phenyl)methanesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)(3,4-dichlorophenyl)methanesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)naphthalene-2-sulfonamide,
(E)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-2-phenylethenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3,5-dichlorobenzenesulfonamide,
3-bromo-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-2,4-dichlorobenzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3,5-bis(trifluoromethyl)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-(2-methoxyphenoxy)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-phenylbenzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-(4-fluorophenyl)benzenesulfonamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)(3,5-dichlorophenyl)methanesulfonamide,
2-(2-tert-butylphenoxy)-N-(3-phenylpropyl)pyridin-3-amine,
N-benzyl-2-(2-tert-butylphenoxy)pyridin-3-amine,
p-tolyl 2-(2-tert-butylphenoxy)pyridin-3-ylcarbamate,
3,5-dichlorobenzyl 2-(2-tert-butylphenoxy)pyridin-3-ylcarbamate,
1-benzoyl-4-(2-phenoxypyridin-3-yl)semicarbazide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-2-p-tolylacetamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-2-(4-chlorophenyl)propanamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-phenylpropanamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-phenylpropiolamide,
N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-2-phenylacetamide,
N1-(2-(2-tert-butylphenoxy)pyridin-3 -yl)-N 3-(4-(trifluoromethoxy)phenyl)malonamide,
benzyl 2-(2-tert-butylphenoxy)pyridin-3-ylcarbamate,
2-(2-(2-tert-butylphenoxy)pyridin-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide, and
2-(2-(2-tert-butylphenoxy)pyridin-3-yl)-N-(4-tert-butylphenyl)acetamide, or a stereoisomer or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

11. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2.

12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3.

13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.

14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5.

15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6.

16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7.

17. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8.

18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 9.