Thrombin or factor Xa inhibitors

FIELD OF THE INVENTION

[0001] This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

[0002] Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

[0003] Therefore, efficacious and specific inhibitors of factor Xa, thrombin, or both are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa, thrombin, or both inhibitors.

SUMMARY OF THE INVENTION

[0004] Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrug thereof.

[0005] It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

[0006] It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

[0007] It is another object of the present invention to provide novel compounds for use in therapy.

[0008] It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of thrombosis or a disease mediated by factor Xa.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0009] [1] Thus, in a first embodiment, the present invention provides a novel compound selected from the group:

[0010] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

[0011] G is selected from the group:

[0012] Ln is a linker which is absent or is selected from O, S, CH2, *CH2NHC(O), *CH(Ra)NHC(O), *CH2NHC(O)CH2, and *CH(Ra)NHC(O)CH2, provided that Ln and M do not form an O—N or S—N bond and the * indicates where Ln is bonded to G;

[0013] M1 is absent or is CHR;

[0014] M2 is N or CRf;

[0015] M3 is N or CRd;

[0016] provided that only one of M2 and M3 is N;

[0017] Ra is selected from C(O)C(O)OR3, C(O)C(O)NR2R2a, and C(O)—A;

[0018] Rb is selected from H, R, phenyl, C1-10 alkyl, and C2-5 alkenyl;

[0019] Rc is selected from H and C1-6 alkyl;

[0020] alternatively, Rb and Rc together are —(CH2)4—;

[0021] Rd is selected from H, F, and Cl;

[0022] Re is selected from H, N(CH3) (CH2CO2H) and S-(5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4);

[0023] alternatively, Rd and Re combine to form —NR3—C(O)—C(R1bR3)—NR3— or —N═CR2—NR3—;

[0024] Rf is selected from H, F, and Cl;

[0025] alternatively, Re and Rf combine to form —NR3—C(R1bR3)—C(O)—NR3— or —NR3—CR2═N—;

[0026] Rg is selected from H, CH2OR3, CH2C(O)OR3, C1-4 alkyl, C(O)NH2, and NH2;

[0027] Rh is selected from H, CH2-phenyl, CH2CH2-phenyl, and CH═CH-phenyl;

[0028] Ri is selected from SO2CH2C(O)OR3, C(O)CH2C(O)OR3, and C(O)OR3;

[0029] R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, benzyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;

[0030] Z is selected from (CR8R9)1-4, (CR8R9)rO (CR8R9)r, (CR8R9)rNR3(CR8R9)r, (CR8R9)rC(O) (CR8R9)r, (CR8R9)rC(O)O(CR8R9)r, (CR8R9)rOC(O)(CR8R9)r, (CR8R9)rC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)(CR8R9)r, (CR8R9)rOC(O)O(CR8R9)r, (CH2)rOC(O)NR3(CR8R9)r, (CR8R9)rNR3C(O)O(CR8R9)r, (CH2)rNR3C(O)NR3(CR8R9)r, (CR8R9)rS(O)p(CR8R9)r, (CR8R9)rS(O)2(CH═CH), (CCR8R9)rSO2NR3 (CR8R9)r, (CR8R9)rNR3SO2 (CR8R9)r, and (CR8R9)rNR3SO2NR3(CR8R9)r, provided that Z does not form a N—N, N—O, N—S, NCH2N, NCH2O, or NCH2S bond with the groups to which Z is attached;

[0031] R1a is absent or selected from —(CH2)r—R1′, —CH═CH—R1′, NHCH2R1″, OCH2R1″, SCH2R1″, NH(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1′;

[0032] R1′ is selected from H, C1-3 alkyl, F, Cl, Er, I, —CN, —CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)p(CH2)rR2b, NR2(CH2)rOR2, C(═NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0033] R1″ is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;

[0034] R1b is selected from H, C1-6 alkyl, and C1-6 alkyl substituted with A;

[0035] R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

[0036] R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 cycloalkylmethyl substituted with 0-2 R4b, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

[0037] R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

[0038] R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

[0039] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0040] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0041] R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0042] R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0043] R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;

[0044] A is selected from:

[0045] C3-10 carbocyclic residue substituted with 0-2 R4, and

[0046] 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0047] A1 is H or A;

[0048] alternatively, A and A1 and the carbon to which they are attached combine to form fluorene;

[0049] A2 is selected from H, A, and CHA3A4;

[0050] A3 is selected from H, A, C1-4 alkyl, and —(CH2)rNR2R2a;

[0051] A4 is H or A;

[0052] B is selected from: H, Y, and X—Y

[0053] X is selected from C1-4 alkylene, —CR2(CR2R2b)(CH2)t—, —C(O)—, —CR2(NR1″R2)—, —CR2(OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —OS(O)2—, —S(O)p—, —S(O)pCR2R2a—, —CR2R2aS(O)p—, —S(O)2NR2—, —NR2S(O)2—, —NR2S(O)2CR2R2a—, —CR2R2aS(O)2NR2—, —NR2S(O)2NR2—, —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)O—, —OC(O)NR2—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—;

[0054] Y is selected from:

[0055] (CH2)rNR2R2a, provided that X—Y do not form a N—N, O—N, or S—N bond,

[0056] C3-10 carbocyclic residue substituted with 0-2 R4a, and

[0057] 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0058] alternatively, Z—A—B combine to form S—C1-6 alkyl;

[0059] R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, C(═N2)NR2R2a, C(═NS(O)2R5)NR2R2a, NHC(═NR2)NR2R2a, C(O)NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NHCH2R1″, OCH2R1″, SCH2R1″, N(CH2)2(CH2)tR1′, O(CH2)2(CH2)tR1′, and S(CH2)2(CH2)tR1″;

[0060] alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

[0061] R4a, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CH2)r—F, (CH2)r—Br, (CH2)r—Cl, Cl, Br, F, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, C(═NR2)R3c, C(═NR2) NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2a, NR2SO2—C1-4 alkyl, C(O)NHSO2—C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;

[0062] alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R5;

[0063] R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;

[0064] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;

[0065] R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;

[0066] R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;

[0067] R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;

[0068] alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0069] R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;

[0070] n, at each occurrence, is selected from 0, 1, 2, and 3;

[0071] m, at each occurrence, is selected from 0, 1, and 2;

[0072] p, at each occurrence, is selected from 0, 1, and 2;

[0073] r, at each occurrence, is selected from 0, 1, 2, and 3;

[0074] s, at each occurrence, is selected from 0, 1, and 2; and,

[0075] t, at each occurrence, is selected from 0, 1, 2, and 3.

[0076] [2] In a preferred embodiment, the present invention provides a novel compound, wherein:

[0077] G is selected from the group:

[0078] [3] In a more preferred embodiment, the present invention provides a novel compound, wherein:

[0079] G is selected from:

[0080] [4] In an even more preferred embodiment, the present invention provides a novel compound, wherein:

[0081] R is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;

[0082] Z is selected from CH2O, OCH2, CH2NH, NHCH2, C(O), CH2C(O), C(O)CH2, NHC(O), C(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, provided that Z does not form a N—N, N—O, NCH2N, or NCH2O bond with ring M or group A;

[0083] A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4;

[0084] phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

[0085] B is selected from: H, Y, and X—Y;

[0086] X is selected from C1-4 alkylene, —C(O)—, —C(═NR)—, —CR2(NR2R2a)—, —C(O)CR2R2a—, —CR2R2aC(O), —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, O, —CR2R2aO—, and —OCR2R2a—;

[0087] Y is NR2R2a or CH2NR2R2a, provided that X—Y do not form a N—N or O—N bond;

[0088] alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;

[0089] cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

[0090] alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

[0091] K is selected from O, S, NH, and N.

[0092] [5] In a still more preferred embodiment, the present invention provides a novel compound, wherein:

[0093] Z is C(O)CH2 and CONH, provided that Z does not form a N—N bond with group A;

[0094] A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,

[0095] B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;

[0096] B is selected from: Y and X—Y;

[0097] X is selected from CH2, —C(O)—, and O;

[0098] Y is NR2R2a or CH2NR2R2a, provided that X—Y does not form an O—N bond;

[0099] alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;

[0100] phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;

[0101] R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

[0102] R2a, at each occurrence, is selected from H, CF3, CH3, CH(CH3)2, cyclopropylmethyl, benzyl, and phenyl;

[0103] alternatively, R2 and R2a combine to form a ring system substituted with 0-2 R4b, the ring system being selected from pyrrolidinyl, piperazinyl and morpholino;

[0104] R4, at each occurrence, is selected from OH, (CH2)rOR2, Cl, F, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;

[0105] R4a is selected from Cl, F, C1-4 alkyl, CF3, (CH2)rNR2R2a, S(O)pR5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;

[0106] R4b, at each occurrence, is selected from OH, Cl, F, CH3, and CF3;

[0107] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0108] R7, at each occurrence, is selected from H, CH3, and CH2CH3; and,

[0109] R8, at each occurrence, is selected from H and CH3.

[0110] [6] In an even further preferred embodiment, the present invention provides a novel compound, wherein:

[0111] A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

[0112] B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 2-(N,N-dimethylaminomethyl)phenyl, 2-(isopropylaminomethyl)phenyl, 2-(cyclopropylaminomethyl)phenyl, 2-(N-pyrrolidinylmethyl)phenyl, 2-(3-hydroxy-N-pyrrolidinylmethyl)phenyl, 4-morpholino, 2-(1′-CF3-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 1-methyl-2-imidazolyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-(N,N-dimethylaminomethyl)imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[0113] [7] In another even more preferred embodiment, the present invention provides a compound of formula:

[0114] Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2, the * indicates where Ln is bonded to G;

[0115] Ra is C(O)C(O)OR3;

[0116] Z is selected from C1-4 alkylene, (CH2)rC(O), and (CH2)rS(O)2;

[0117] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0118] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0119] R2b, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0120] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0121] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0122] A is C5-6 carbocyclic residue substituted with 0-2 R4;

[0123] R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0124] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0125] p, at each occurrence, is selected from 0, 1, and 2; and,

[0126] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0127] [8] In another still more preferred embodiment, the present invention provides a compound wherein:

[0128] Ln is *CH(Ra)NHC(O)CH2;

[0129] Ra is C(O)C(O)OH;

[0130] Z is selected from CH2, (CH2)2C(O), and CH2S(O)2;

[0131] A is cyclohexyl or phenyl and is substituted with 0-1 R4;

[0132] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,

[0133] r, at each occurrence, is selected from 0, 1, and 2.

[0134] [9] In another even more preferred embodiment, the present invention provides a compound of formula:

[0135] Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2, the * indicates where Ln is bonded to G;

[0136] Ra is C(O)C(O)OR3;

[0137] R is H or NH2;

[0138] Z is selected from C1-4 alkylene, (CH2)rC(O) and (CH2)rS(O)2;

[0139] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0140] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0141] R2b, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0142] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0143] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0144] A is a C5-6 carbocyclic residue substituted with 0-2 R4;

[0145] R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0146] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0147] p, at each occurrence, is selected from 0, 1, and 2; and,

[0148] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0149] [10] In another still more preferred embodiment, the present invention provides a compound wherein:

[0150] Ln is *CH(Ra)NHC(O)CH2;

[0151] R is H;

[0152] Ra is C(O)C(O)OH;

[0153] Z is selected from CH2, (CH2)2C(O), and CH2S(O)2;

[0154] A is cyclohexyl or phenyl and is substituted with 0-1 R4;

[0155] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0156] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0157] [11] In another even more preferred embodiment, the present invention provides a compound of formula:

[0158] Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2, the * indicates where Ln is bonded to G;

[0159] R is H or NH2;

[0160] Ra is C(O)C(O)OR3;

[0161] Z is C1-4 alkylene;

[0162] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0163] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0164] R2b, at each occurrence, is selected from H. C1-6 alkyl, benzyl, and phenyl;

[0165] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0166] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0167] A is phenyl substituted with 0-2 R4;

[0168] R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0169] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0170] p, at each occurrence, is selected from 0, 1, and 2; and,

[0171] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0172] [12] In another still more preferred embodiment, the present invention provides a compound wherein:

[0173] Ln is *CH(Ra)NHC(O)CH2;

[0174] R is NH2;

[0175] Ra is C(O)C(O)OH;

[0176] Z is CH2;

[0177] A is phenyl substituted with 0-1 R4;

[0178] R4, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,

[0179] r, at each occurrence, is selected from 0, 1, and 2.

[0180] [13] In another even more preferred embodiment, the present invention provides a compound of formula:

[0181] Ln is *CH2NHC(O) or *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;

[0182] Ra is selected from C(O)C(O)OR3 and C(O)—A;

[0183] Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;

[0184] Rc is selected from H and C1-6 alkyl;

[0185] alternatively, Rb and Rc together are —(CH2)4—;

[0186] Z is (CR8R9)1-4;

[0187] R2, at each occurrence, is selected from H, CF3, and C1-6 alkyl;

[0188] R2a, at each occurrence, is selected from H, CF3, and C1-6 alkyl;

[0189] R2b, at each occurrence, is selected from H, CF3, and C1-6 alkyl;

[0190] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0191] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0192] A is selected from:

[0193] C6-10 aromatic carbocyclic residue substituted with 0-2 R4, and

[0194] 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0195] R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SC2NR2R2a, S(O)pR5, and CF3;

[0196] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0197] R8, at each occurrence, is selected from H, C1-6 alkyl and phenyl;

[0198] R9, at each occurrence, is selected from H, C1-6 alkyl and phenyl;

[0199] p, at each occurrence, is selected from 0, 1, and 2;

[0200] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0201] [14] In another still more preferred embodiment, the present invention provides a compound wherein:

[0202] Ln is *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;

[0203] Ra is C(O)C(O)OH or C(O)-(benzothiazol-2-yl);

[0204] Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;

[0205] Rc is selected from H and C1-6 alkyl;

[0206] alternatively, Rb and Rc together are —(CH2)4—;

[0207] Z is (CR8H)1-2;

[0208] A is selected from phenyl, naphthyl, and thienyl, and A is substituted with 0-1 R4;

[0209] R4, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0210] R8, at each occurrence, is selected from H, methyl and phenyl; and,

[0211] r, at each occurrence, is selected from 0, 1, and 2.

[0212] [15] In another even more preferred embodiment, the present invention provides a compound of formula:

[0213] Ln is *CH2NHC(O) or *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;

[0214] Ra is selected from C(O)C(O)OR3 and C(O)—A;

[0215] Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;

[0216] Rc is selected from H and C1-6 alkyl;

[0217] alternatively, Rb and Rc together are —(CH2)4—;

[0218] R is selected from H, benzyl, C1-4 alkyl, and NH2;

[0219] Z is (CR8R9)1-4;

[0220] R2, at each occurrence, is selected from H, CF3, and C1-6 alkyl;

[0221] R2a at each occurrence, is selected from H, CF3, and C1-6 is alkyl;

[0222] R2b, at each occurrence, is selected from H, CF3, and C1-6 alkyl;

[0223] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0224] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0225] A is selected from:

[0226] C6-10 aromatic ring substituted with 0-2 R4, and

[0227] 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0228] R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0229] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0230] R8, at each occurrence, is selected from H, C1-6 alkyl and phenyl;

[0231] R9, at each occurrence, is selected from H, C1-6 alkyl and phenyl;

[0232] p, at each occurrence, is selected from 0, 1, and 2;

[0233] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0234] [16] In another still more preferred embodiment, the present invention provides a compound wherein:

[0235] Ln is *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;

[0236] Ra is C(O)C(O)OH or C(O)-(benzothiazol-2-yl);

[0237] Rb is selected from H, phenyl, C1-10 alkyl, and C2-5 alkenyl;

[0238] Rc is selected from H and C1-6 alkyl;

[0239] alternatively, Rb and Rc together are —(CH2)4—;

[0240] Z is (CR8H)1-2;

[0241] A is selected from phenyl, naphthyl, and thienyl, and A is substituted with 0-1 R4;

[0242] R4, at each occurrence, is selected from H. OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0243] R8, at each occurrence, is selected from H. C1-6 alkyl and phenyl;

[0244] r, at each occurrence, is selected from 0, 1, and 2.

[0245] [17] In another even more preferred embodiment, the present invention provides a compound of formula:

[0246] Ln is *CH2NHC(O) or *CH(Ra)NHC(O) and the * indicates where Ln is bonded to G;

[0247] R1a is selected from —(CH2)r—R1′ and NHCH2R1″;

[0248] R1′ is selected from H, OR2, NR2R2a, and NR2SO2(CH2)rR2b;

[0249] R1″ is selected from C(O)NR2R2a, S(O)2R2b, and SO2NR2R2a;

[0250] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0251] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0252] R2b, at each occurrence, is selected from C1-4 alkoxy, C1-6 alkyl, benzyl, phenyl substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;

[0253] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0254] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0255] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0256] A is phenyl substituted with 0-2 R4;

[0257] A1 is H or A;

[0258] alternatively, A and A1 and the carbon to which they are attached combine to form fluorene;

[0259] A2 is selected from H, A, and CHA3A4;

[0260] A3 is selected from H, A, C1-4 alkyl, and —(CH2)rNR2R2a;

[0261] A4 is H or A;

[0262] R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0263] R4b, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0264] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0265] p, at each occurrence, is selected from 0, 1, and 2;

[0266] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0267] [18] In another still more preferred embodiment, the present invention provides a compound wherein:

[0268] Ln is *CH2NHC(O) and the * indicates where Ln is bonded to G;

[0269] R1a is selected from —(CH2)r—R1′ and NHCH2R1″;

[0270] R1′ is selected from OH, NR2R2a, and NR2SO2(CH2)rR2b;

[0271] R1″ is selected from C(O)NR2R2a, S(O)2R2b, and SO2NR2R2a;

[0272] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0273] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0274] R2b, at each occurrence, is selected from C1-4 alkoxy, C1-6 alkyl, benzyl, phenyl substituted with 0-1 R4b, and pyrrolidinyl substituted with 0-1 R4b;

[0275] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0276] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a piperidine ring substituted with 0-1 R4b;

[0277] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0278] R4b, at each occurrence, is selected from H, ═O, OH, F, Cl, C1-4 alkyl, and NH2; and,

[0279] r, at each occurrence, is selected from 0, 1, and 2.

[0280] [19] In another even more preferred embodiment, the present invention provides a compound of formula:

[0281] Ln is O or S;

[0282] M2 is N or CRf;

[0283] M3 is N or CRd;

[0284] provided that only one of M2 and M3 is N;

[0285] Re is selected from H, N(CH3)(CH2CO2H) and S-(5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4);

[0286] Rd is selected from H, F. and Cl;

[0287] alternatively, Rd and Re combine to form —NR3—C(O)—C(R1bR3)—NR3— or —N═CR2—NR3—;

[0288] Rf is selected from H, F, and Cl;

[0289] alternatively, Re and Rf combine to form —NR3—C(R1bR3)—C(O)—NR3— or —NR3—CR2═N—;

[0290] Z is O, provided that Z does not form a N—O or NCH2O bond with the groups to which Z is attached;

[0291] R1b is selected from H, C1-6 alkyl, and C1-6 alkyl substituted with A;

[0292] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0293] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0294] R2b, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0295] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0296] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0297] A is selected from:

[0298] C5-6 carbocyclic residue substituted with 0-2 R4, and

[0299] 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0300] B is H or Y;

[0301] Y is selected from:

[0302] C5-6 carbocyclic residue substituted with 0-2 R4a, and

[0303] 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0304] R4, at each occurrence, is selected from H, ═O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(═NR2)NR2R2a, NHC(═NR2) NR2R2a, SO2NR2R2a, and CF3;

[0305] R4a, at each occurrence, is selected from H, ═O, (CH2)rOR2, (CH2)r—F, (CH2)r—Br, (CH2)r—Cl, Cl, Br, F, I, C1-4 alkyl, —CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(═NR2)NR2R2a, NHC(═NR2)NR2R2a, SO2NR2R2a, and CF3; and,

[0306] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0307] [20] In another still more preferred embodiment, the present invention provides a compound wherein:

[0308] Ln is O;

[0309] Re is N(CH3)(CH2CO2H);

[0310] Rd is H or F;

[0311] alternatively, Rd and Re combine to form —NR3—C(O)—C(R1bR3)—NR3— or —N═CR2—NR3—;

[0312] Rf is H or F;

[0313] alternatively, Re and Rf combine to form —NR3—C(R1bR3)—C(O)—NR3— or —NR3—CR2═N—;

[0314] R1b is selected from H, C1-2 alkyl and benzyl;

[0315] A is phenyl substituted with 0-2 R4;

[0316] B is H or Y;

[0317] Y is 5 membered heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0318] R4, at each occurrence, is selected from H, C1-4 alkyl, and NR2R2a; and,

[0319] R4a, at each occurrence, is selected from H, C1-4 alkyl, and NR2R2a.

[0320] [21] In another even more preferred embodiment, the present invention provides a compound of formula:

[0321] Ln is *CH2NHC(O)CH2 or *CH(Ra)NHC(O)CH2 and the * indicates where Ln is bonded to G;

[0322] M1 is absent or is CHR;

[0323] R is selected from H, Cl, F, Br, I, OR3, C1-4 alkyl, OCF3, CF3, and NH2;

[0324] Z is C1-4 alkylene;

[0325] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0326] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0327] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0328] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0329] A is selected from:

[0330] C3-6 carbocyclic residue substituted with 0-2 R4, and

[0331] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0332] R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,

[0333] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0334] [22] In another still more preferred embodiment, the present invention provides a compound wherein:

[0335] Ln is *CH2NHC(O)CH2 and the * indicates where Ln is bonded to G.;

[0336] M1 is absent;

[0337] R is selected from H and C1-4 alkyl;

[0338] Z is CH2;

[0339] A is C3-6 carbocyclic residue substituted with 0-1 R4;

[0340] R4, at each occurrence, is selected from H, C1-4 alkyl, (CH2)rNR2R2a, and CF3; and,

[0341] r, at each occurrence, is selected from 0, 1, and 2.

[0342] [23] In another even more preferred embodiment, the present invention provides a compound of formula:

[0343] Ln is absent;

[0344] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0345] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0346] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0347] X is SO2 or SO2(CH═CH);

[0348] Y is selected from:

[0349] C6-10 carbocyclic residue substituted with 0-2 R4a, and

[0350] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0351] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0352] R4a, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,

[0353] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0354] [24] In another still more preferred embodiment, the present invention provides a compound wherein:

[0355] X is SO2;

[0356] Y is selected from phenyl substituted with 0-2 R4a and naphthyl substituted with 0-2 R4a;

[0357] R4, at each occurrence, is selected from H, ═O, OH, CH2OH, F, Cl, Br, C1-4 alkyl, C(O)NR2R2a, and C(O)R2c;

[0358] R4a, at each occurrence, is selected from H, OH, CH2OH, F, Cl, Br, C1-4 alkyl, and C(O)R2c; and,

[0359] r, at each occurrence, is selected from 0, 1, and 2.

[0360] [25] In another even more preferred embodiment, the present invention provides a compound of formula:

[0361] Ln is absent;

[0362] R2, at each occurrence, is selected from H. C1-6 alkyl, benzyl, and phenyl;

[0363] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0364] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0365] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N. O, and S;

[0366] X is SO2 or SO2(CH═CH);

[0367] Y is selected from:

[0368] C6-10 carbocyclic residue substituted with 0-2 R4a, and

[0369] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0370] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0371] R4a, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0372] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0373] [26] In another still more preferred embodiment, the present invention provides a compound wherein:

[0374] X is SO2;

[0375] Y is phenyl substituted with 0-2 R4a or naphthyl substituted with 0-2 R4a;

[0376] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O)R2c, and C(O)NR2R2a;

[0377] R4a, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O)R2c, and C(O)NR2R2a;

[0378] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0379] [27] In another even more preferred embodiment, the present invention provides a compound of formula:

[0380] Ln is absent;

[0381] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0382] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0383] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0384] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0385] X is SO2 or SO2(CH═CH);

[0386] Y is selected from:

[0387] C6-10 carbocyclic residue substituted with 0-2 R4a, and

[0388] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0389] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0390] R4a, at each occurrence, is selected from H, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0391] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0392] [28] In another still more preferred embodiment, the present invention provides a compound wherein:

[0393] X is SO2;

[0394] Y is phenyl substituted with 0-2 R4a or naphthyl substituted with 0-2 R4a;

[0395] R4, at each occurrence, is selected from H, ═O, OR2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O)R2c, and C(O)NR2R2a;

[0396] R4a, at each occurrence, is selected from H, R2, CH2OR2, F, Cl, Br, I, C1-4 alkyl, NH2, (CH2)rC(O) R2c, and C(O)NR2R2a; and,

[0397] r, at each occurrence, is selected from 0, 1, and 2.

[0398] [29] In another even more preferred embodiment, the present invention provides a compound of formula:

[0399] Ra is C(O)-(6 membered heterocyclic system containing 1 N atom and substituted with 0-2 R4);

[0400] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0401] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0402] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0403] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0404] A is a 10 membered bicyclic heterocyclic system containing 1 N atom and substituted with 0-2 R4;

[0405] B is H or Y;

[0406] Y is selected from:

[0407] C3-6 carbocyclic residue substituted with 0-2 R4a, and

[0408] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0409] R4, at each occurrence, is selected from H, ═O, OR2, F, Cl, Br, I, C1-4 alkyl, NR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, and CF3;

[0410] R4a, at each occurrence, is selected from H, ═O, OR2, F, Cl, Br, I, C1-4 alkyl, NR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, and CF3;

[0411] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0412] [30] In a still more preferred embodiment, the present invention provides a compound wherein:

[0413] Ra is C(O)—(N-1,2,3,6-tetrahydropyridine substituted with CO2H);

[0414] alternatively, Ra is C(O)—(N-1,2,3,6-tetrahydropyridine substituted with CH3);

[0415] A is 1,2,3,4-tetrahydroisoquinoline substituted with 1-2 R4;

[0416] B is H;

[0417] R4, at each occurrence, is selected from H, methyl, ═O, OR2, F, Cl, Br, I, C1-4 alkyl, NR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3;

[0418] r, at each occurrence, is selected from 0, 1, and 2.

[0419] [31] In another even more preferred embodiment, the present invention provides a compound of formula:

[0420] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0421] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0422] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0423] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0424] X iS OSO2;

[0425] Y is selected from:

[0426] C6-10 aromatic ring substituted with 0-2 R4a, and

[0427] 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0428] R4 is H;

[0429] R4a, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, and CF3; and,

[0430] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0431] [32] In a still more preferred embodiment, the present invention provides a compound wherein:

[0432] R is methyl;

[0433] Y is selected from phenyl substituted with 0-2 R4a, naphtyl substituted with 0-2 R4a, and quinolinyl substituted with 0-2 R4a;

[0434] R4a, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, (CH2)rNR2R2a, and CF3; and,

[0435] r, at each occurrence, is selected from 0, 1, and 2.

[0436] [33] In another more preferred embodiment, the present invention provides a compound of formula:

[0437] Rg is selected from H, CH2OR3, CH2C(O)OR3, C1-4 alkyl, C(O)NH2, and NH2;

[0438] Rh is selected from H, CH2-phenyl, CH2CH2-phenyl, and CH═CH-phenyl;

[0439] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0440] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0441] R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, benzyl, and phenyl;

[0442] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0443] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0444] A is selected from:

[0445] C6-10 aromatic ring substituted with 0-2 R4, and

[0446] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;

[0447] B is H or Y;

[0448] Y is selected from:

[0449] C6-10 aromatic ring substituted with 0-2 R4a, and

[0450] 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;

[0451] R4, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, —CN, (CH2)rNR2R2a, (CH2)rC(O)R2c, S(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0452] R4a, at each occurrence, is selected from H, (CH2)rOR2, Cl, Br, F, I, C1-4 alkyl, —CN, (CH2)rNR2R2a, (CH2)rC(O)R2c, C(O)NR2R2a, SO2NR2R2a, S(O)pR5, and CF3;

[0453] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0454] p, at each occurrence, is selected from 0, 1, and 2; and,

[0455] r, at each occurrence, is selected from 0, 1, 2, and 3.

[0456] [34] In a still more preferred embodiment, the present invention provides a compound wherein:

[0457] Rg is selected from CH2OR3, and CH2C(O)OCH3;

[0458] Rh is selected from CH2-phenyl, CH2CH2-phenyl, and CH═CH-phenyl;

[0459] A is phenyl;

[0460] B is Y;

[0461] Y is phenyl substituted with 0-2 R4a;

[0462] R4a, at each occurrence, is selected from H, OR2, Cl, Br, F, I, C1-4 alkyl, (CH2)rNR2R2a, C(O)NR2R2a, and CF3; and,

[0463] r, at each occurrence, is selected from 0, 1, and 2.

[0464] [35] In another more preferred embodiment, the present invention provides a compound of formula:

[0465] Ri is selected from SO2CH2C(O)OR3, C(O)CH2C(O)OR3, and C(O)OR3;

[0466] X is O;

[0467] Y is pyrrolidinyl substituted with 1-2 R4a or piperidinyl substituted with 1-2 R4a;

[0468] R2, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0469] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0470] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0471] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0472] R4, at each occurrence, is selected from H, F, Cl, Br, I, C1-4 alkyl, NR2R2a, and CF3; and,

[0473] R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(═NR2)CH3.

[0474] [36] In a still more preferred embodiment, the present invention provides a compound wherein:

[0475] Ri is selected from SO2CH2C(O)OR3 and C(O)CH2C(O)OR3;

[0476] Y is piperidinyl substituted with 1-2 R4a;

[0477] R3, at each occurrence, is selected from H and C1-4 alkyl;

[0478] R4 is H; and,

[0479] R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(═NR2)CH3.

[0480] In another more preferred embodiment, the present invention provides a compound of formula:

[0481] Ri is selected from SO2CH2C(O)OR3, C(O)CH2C(O)OR3, and C(O)OR3;

[0482] X is O;

[0483] Y is pyrrolidinyl substituted with 1-2 R4a or piperidinyl substituted with 1-2 R4a;

[0484] R2 at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0485] R2a, at each occurrence, is selected from H, C1-6 alkyl, benzyl, and phenyl;

[0486] alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

[0487] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0488] R4, at each occurrence, is selected from H, F, Cl, Br, I, C1-4 alkyl, NR2R2a, and CF3; and,

[0489] R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(═NR2)CH3.

[0490] In a still more preferred embodiment, the present invention provides a compound wherein:

[0491] Ri is selected from SO2CH2C(O)OR3 and C(O)CH2C(O)OR3;

[0492] Y is piperidinyl substituted with 1-2 R4a;

[0493] R3, at each occurrence, is selected from H and C1-4 alkyl;

[0494] R4 is H; and,

[0495] R4a, at each occurrence, is selected from H, C1-4 alkyl, CH2NR2R2a, and C(═NR2)CH3.

[0496] In a second embodiment, the present invention provides compounds selected from the group:

[0497] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

[0498] G is selected from:

[0499] Ra is selected from C(O)C(O)OH and C(O)(benzothiazol-2-yl);

[0500] Rg is selected from H, CH2OR3, CH2C(O)OR3, C1-4 alkyl, C(O)NH2, and NH2;

[0501] Rh is selected from H, CH2-phenyl, CH2CH2-phenyl, and CH═CH-phenyl;

[0502] Ri is selected from SO2CH2C(O)OH and C(O)CH2C(O)OH, and C(O)OR3;

[0503] R, at each occurrence, is selected from H, methyl, ethyl, benzyl, and NH2;

[0504] R2, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

[0505] R2a, at each occurrence, is selected from H, CF3, CH3, benzyl, and phenyl;

[0506] alternatively, R2 and R2a combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

[0507] R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;

[0508] Z is C(O)CH2 or CONH;

[0509] A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4; and,

[0510] B is selected from Y, X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R4a;

[0511] R4, at each occurrence, is selected from OH, (CH2)rOR2, halo, C1-4 alkyl, (CH2)rNR2R2a, and (CF2)rCF3;

[0512] R4a is selected from C1-4 alkyl, CF3, S(O)2R5, SO2NR2R2a, and 1-CF3-tetrazol-2-yl;

[0513] R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;

[0514] X is CH2 or C(O);

[0515] Y is selected from NR2R2a and CH2NR2R2a;

[0516] p is selected from 0, 1, and 2; and,

[0517] r is selected from 0, 1, and 2.

[0518] In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of present invention or a pharmaceutically acceptable salt form thereof.

[0519] In another embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.

[0520] Definitions

[0521] 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. Many geometric isomers of olefins, C═N double bonds, and the like 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. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

[0522] “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

[0523] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0524] When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0525] 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.

[0526] 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. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. “Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. “Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.

[0527] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

[0528] As used herein, “carbocycle” or “carbocyclic group” 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, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

[0529] As used herein, the term “heterocycle” or “heterocyclic group” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom 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. A nitrogen 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. As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

[0530] Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

[0531] 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.

[0532] 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 residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 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, nitric and the like; 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, isethionic, and the like.

[0533] 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, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0534] “Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.

[0535] “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.

[0536] “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit factor Xa or thrombin or treat diseases related to factor Xa or thrombin in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of factor Xa or thrombin) 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 suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

[0537] Synthesis

[0538] The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

[0539] Compounds of the above formulas can be prepared by coupling corresponding acid and amine precursors. The acid precursors can be prepared as shown in WO98/28326, WO 98/09987, WO/28326, WO96/19483, and WO98/05333, the contents of which are incorporated herein by reference. The G—CH(Ra)NH2 precursors can be prepared as shown in the above-identified publications or as shown in the present application.

[0540] Compounds of the above formulas can be prepared by coupling corresponding acid and amine precursors. The acid precursors can be prepared as shown in WO98/05333, the contents of which are incorporated herein by reference. The G—CH(Ra)NH2 precursors can be prepared as shown in the above-identified publications or as shown in the present application.

[0541] Compounds of the above formula can be prepared by coupling the corresponding acid and amine precursors. The acid precursors can be prepared as shown in U.S. Pat. No. 5,798,377, the contents of which are incorporated herein by reference. The G—CH2NH2 precursors can be prepared as shown in the above-identified publication or as shown in the present application.

[0542] Compounds of the above formula can be prepared by coupling corresponding G-leaving group and alcohol-pyridyl or thiol-pyridyl precursors. The alcohol and thio precursors can be prepared as shown in U.S. Pat. No. 5,693,641, WO96/28427, WO97/29067, WO98/07725, and WO98/15547, the contents of which are incorporated herein by reference. The G-leaving group precursors can be prepared as shown in the above-identified publications or as shown in the present application. Alternatively, the compounds of the above formula can be prepared by displacing a leaving group from the pyridyl precursor with the corresponding G-OH precursor. Leaving groups for this type of coupling can be SCH3 or SO2CH3.

[0543] Compounds of the above formula can be prepared by coupling corresponding acid and amine precursors. The acid precursors can be prepared as shown in WO98/17274, the contents of which are incorporated herein by reference. The G—CH2NH2 precursors can be prepared as shown in the above-identified publication or as shown in the present application.

[0544] Compounds of the above formula can be prepared by coupling corresponding G-benzoic acid and piperazine precursors. The G-benzoic acid precursors can be prepared similarity to the methods shown in WO98/21188, the contents of which are incorporated herein by reference. For example, the G-benzoic acid precursors can be prepared by coupling an activated G (e.g., a metallated ring) with a leaving group-benzoic acid (e.g., halo-benzoic acid) as shown in the above-identified publication. The piperazine precursors can be prepared by coupling of the desired piperazine with the desired X—Y group, wherein X contains a leaving group, as shown in the above-identified application or in the present application.

[0545] Compounds of the above formulas can be prepared by coupling corresponding benzoic acid and piperazine precursors. The G-piperidinyl acid or G-piperazinyl acid precursors can be prepared similarity to the methods shown in WO96/10022, the contents of which are incorporated herein by reference. For example, the G-piperidinyl acid or G-piperazinyl acid precursors can be prepared by coupling a G-leaving group (e.g., G-halogen) with a piperidinyl acid or piperazinyl acid as shown in the above-identified publication. The piperidine and piperazine precursors can be prepared by coupling of the desired piperazine with the desired X—Y group, wherein X contains a leaving group, as shown in the above-identified application or in the present application.

[0546] Compounds of the above formula can be prepared by coupling corresponding sulfonic acid and amine precursors. The sulfonic acid precursors can be prepared as shown in WO96/33993, the contents of which are incorporated herein by reference. The G—CH2CH(Ra)NH2 precursors can be prepared as shown in the above-identified publication or as shown in the present application.

[0547] Compounds of the above formula can be prepared by coupling corresponding G—CHO or G—CH2Br and (Rg)CH2CH2(Rh)N(R3)C(O)—A—B precursors. The (Rg)CH2CH2(Rh)N(R3)C(O)—A—B precursors can be prepared as shown in WO97/24118, the contents of which are incorporated herein by reference. The G—CHO and G—CH2Br precursors can be prepared as shown in the above-identified publication or as shown in the present application.

[0548] Compounds of the above formula can be prepared by coupling corresponding G—(CH2)3-leaving group and ester precursors. The ester precursors can be prepared as shown in EP/0540051, the contents of which are incorporated herein by reference. The G—(CH2)3-leaving group precursors can be prepared as shown in the above-identified publication or other publications described herein or as shown in the present application.

[0549] Compounds of the above formula when G contains an amine linker can be prepared by displacing a leaving group off of the remainder of the molecule with corresponding G-amine precursor. The remainder of the molecule can be prepared as shown in JP10/1467, the contents of which are incorporated herein by reference. The G—NH2 precursors can be prepared as shown in the above-identified publications or as shown in the present application.

[0550] Compounds of the above formula can be prepared by coupling corresponding G—(CH2)3-leaving group and phenol precursors. The phenol precursors can be prepared as shown in WO97/36580, the contents of which are incorporated herein by reference or as shown in the present application. The G—(CH2)3-leaving group precursors can be prepared as shown in the above-identified publication or other publications described herein or as shown in the present application.

[0551] Compounds of the above formulas can be prepared by coupling corresponding aniline and G—(CH2)3-leaving group or G—(CH2)2CO2H precursors. The aniline precursors can be prepared as shown in EP/0540051, JP10/1467, and WO96/16940, the contents of which are incorporated herein by reference. The G—(CH2)3-leaving group or G—(CH2)2CO2H precursors can be prepared as shown in the above-identified publication or other publications described herein or as shown in the present application.

[0552] Many of the compounds of the present invention can be prepared from G—NH2 where G represents a residue which is either the P1 residue described above, a suitably protected form of the P1 residue, or an intermediate which can be transformed at a later stage of the synthesis into the P1 residue. Scheme I describes procedures by which the amino residue of G—NH2 can be transformed into a variety of different functionalities which are useful for assembling the compounds of the present invention. G—NH2 I can be diazotized with sodium nitrite in the presence of aqueous sulfuric acid to produce the hydroxy derivative II. Diazotization of I in acidic media followed by treatment with copper (I) bromide affords the bromo derivative III. The bromo derivative is a very useful intermediate for further functionalization. Treatment of III with magnesium metal generates a Grignard reagent which can react with suitably protected bromoglycinate derivatives to afford amino acid derivatives IV. There are a wide variety of methods available for introducing simple carbon-atom based functionality starting with bromide III. Transmetallation with an organolithium reagent such as tert-butyllithium or n-butyllithium is readily accomplished at low temperature. The formed organolithium species can react with a wide variety of electrophiles. For example, reaction with dimethylformamide produces the aldehyde derivative V, while reaction with an alkyl chloroformate or an alkyl cyanoformate produces an ester derivative. The ester functionality can be reduced with a variety of hydride reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride to afford the alcohol VI. The alcohol VI can also be prepared by reduction of aldehyde V, such as with sodium borohydride. The bromide III can also react through palladium-mediated processes. For example, reaction of III with an alcohol or amine and a catalyst such as tetrakis-triphenylphosphine palladium under a carbon monoxide atmosphere leads to esters G—CO2R or amides G—CONR2 via a carbonyl insertion reaction. A particularly useful amide G—CONR2 available by this procedure is the N-methyl-N-methoxy amide, obtained when N-methyl-N-methoxyamine is used in the carbonyl insertion reaction. This amide is readily reduced to aldehyde V with hydride reducing agents such as diisobutylaluminum hydride. The alcohol VI, readily available by a variety of methods as described above can be converted to the bromide derivative VII by many methods, such as by treatment with carbon tetrabromide and triphenylphosphine. Another method for the preparation of bromide VII, not shown in Scheme I, involves the radical bromination of an intermediate G—CH3, which is readily available by methods known to those skilled in the art of organic synthesis. This radical bromination is readily accomplished by treating G—CH3 with N-bromosuccinimide in refluxing carbon tetrachloride in the presence of a radical initiator such as AIBN. The bromide VII is a particularly useful intermediate for the preparation of the compounds of the present invention. Displacement of the bromide can be accomplished by treatment with sodium or potassium cyanide in a solvent such as DMF or DMSO at room temperature or elevated temperature to give a cyano derivative. Reduction of the nitrile, such as by catalytic hydrogenation or by treatment with sodium borohydride and cobalt (II) chloride, gives the amino derivative VIII. The bromide can also be displaced by appropriate N-protected glycinates, such as N-(diphenylmethylene)glycine ethyl ester, to give the amino acid derivatives IX. This reaction is accomplished by heating VII and the glycinate in the presence of a base such as potassium carbonate and a quaternary ammonium salt such as tetrabutylammonium bromide in a solvent such as acetonitrile. The bromide can also be displaced with sodium azide in a solvent such as DMF or DMSO at elevated temperatures to give an azide intermediate. The azide is readily reduced by a variety of reducing agents, such as by catalytic hydrogenation or by tin (II) chloride, to afford the amino derivative XI. A variety of other methods are available for the preparation of the amino derivative XI. For example, reductive amination of aldehyde V with ammonium acetate and sodium cyanoborohydride affords XI. Alternatively, the amine G—NH2 I can be diazotized as described above and reacted with copper (I) cyanide to afford the nitrile X. The nitrile can be reduced to form amine XI by a variety of methods, such as by catalytic hydrogenation or by reduction with sodium borohydride in the presence of cobalt (II) chloride. A variety of other methods for the preparation of the intermediates described in Scheme I are available and are known to those skilled in the art. The particular method used for the preparation of the required intermediates will depend on additional functionality present on group “G”, and it will be appreciated by those skilled in the art that certain protecting group strategies may be required and that reaction conditions and the order of steps may require modification.

[0553] The compound wherein G is a 2,5-bis(aminomethyl)phenyl group can be prepared from commercially available amino-terephthalate as shown in the Scheme II below.

[0554] The amino group can be further manipulated as described in Scheme I above.

[0555] Scheme III describes the preparation of mono-protected 2-methylaminoaniline intermediates.

[0556] The following are some examples of conditions required for selective protection of the benzylamine functionality.

1AcylatingSolvent andResulting -AgentTrialkylamineTemperatureP.G.1 equivilenttriethylamineCH2Cl2, 0° C.-C(O)CF3of (TFA)2O1 equivilentN-methyl-CHCl3, 0° C.-C(O)O-t-Buofmorpholine(Boc)2O1 equivilentN-methyl-CHCl3, 0° C.-C(O)OCH2PhofmorpholineCbz-Cl

[0557] The mono-protected 2-methylaminoaniline intermediates required to make the 2-methylaminophenyl analogs of this invention can be prepared from the known anthranilic acids by the route outlined in Scheme IV. The anthranilic acid is simultaneously reduced to the benzyl alcohol and N-protected by formation of the mixed anhydride/N-carbamoyl compound followed by selective reduction of the anhydride functionality with aqueous sodium borohydride.

[0558] The benzylalcohol is then transformed to the benzylazide by a two-step sequence involving methanesulfonate ester formation followed by displacement of the sulfonate ester with sodium azide in dimethylformamide. The 2-methylaminoaniline can be obtained from the benzylazide by removal of the carbamoyl group with ethanolic sodium hydroxide followed by catalytic reduction of the azide group.

[0559] Representitive methods for the selective protection of the more reactive benzylamine functionality with a few of the protecting groups (—P.G.) that may be contemplated for the realization of this invention are illustrated in the above table.

[0560] Scheme IV describes the preparation of 1,4-disubstituted-6-aminophthalazine intermediates.

[0561] Synthesis of 1,4-disubstituted-6-aminophthalazines in which the 1 and 4-positions may be a protected amine could be accomplished starting from the commercially available 3,4-dicyanonitrobenzene. Addition of hydrazine to bis-nitrile would form the phthalazine core. Suitable protection and reduction of the aryl nitro group would provide the desired compound.

[0562] Scheme V describes the preparation of 6-amino-2-aminoquinoline intermediates.

[0563] Scheme VI describes the preparation of 7-amino-2-aminoquinoline intermediates.

[0564] Scheme VII describes the preparation of 6-aminoquinazoline intermediates.

[0565] Synthesis of 6-aminoquinazolines in which the 2-position may be a hydrogen, a protected amine, or an alkyl group and the 4-position is a protected amine could be accomplished starting from commercially available 3-cyano-4-fluoronitrobenzene. Reaction of guanidine or amidine nucleophiles at the nitrile followed by fluorine displacement to ring closure would yield the quinazoline core (J. Heterocyclic Chem., 1991, 28, 1357). Suitable protection and reduction of the aryl nitro group would provide the title compound.

[0566] Scheme VIII describes the preparation of 7-aminoquinazoline intermediates.

[0567] Synthesis of 7-aminoquinazolines in which the 2-position may be a hydrogen, a protected amine, or an alkyl group and the 4-position is a protected amine could be accomplished starting from commercially available 2-fluoro-4-nitrobenzoic acid. Conversion of carboxylic acid to nitrile via standard manipulations would give 2-fluoro-4-nitrobenzonitrile. Reaction of guanidine or amidine nucleophiles at the nitrile followed by fluorine displacement to ring closure would yield the quinazoline core (J. Heterocyclic Chem., 1991, 28, 1357). Suitable protection and reduction of the aryl nitro group would provide the 7-aminoquinazoline.

[0568] Scheme IX describes the preparation of 7-aminoisoquinazoline intermediates.

[0569] Synthesis of 7-aminoisoquinolines in which the 1 or 4-position may be a protected amine could be accomplished from the corresponding known 7-nitroisoquinoline by published methods (see for example, U.S. Pat. No. 4,673,676). Suitable protection and reduction of the aryl nitro group would provide the 7-aminoisoquinoline.

[0570] Scheme X describes the preparation of 6-aminoisoquinazoline intermediates.

[0571] Synthesis of 6-aminoisoquinolines in which the 1 or 4-position may be a protected amine could be accomplished starting from commercially available 1,2,3,4-tetrahydroisoquinoline. Conversion to the known 6-nitro isoquinoline (Chem. Pharm. Bull. 1958, 6, 497, 499) and on to the 1- and 4-amino derivatives (see for example U.S. Pat. No. 4,673,676) followed by suitable protection and reduction of the aryl nitro group would provide the desired compound.

[0572] Scheme XI describes the preparation of 7-aminophthalazine intermediates.

[0573] Synthesis of 7-aminophthalazines in which the 1-position may be a protected amine could be accomplished starting from commercially available 2-cyano-4-nitrotoluene. Bromination of tolyl methyl to give a benzyl bromide followed by displacement with hydrazine would afford benzyl hydazine intermediate. Ring closure by subsequent addition to the nitrile under thermal conditions would yield the phthalazine core. Suitable protection and reduction of the aryl nitro group would provide the desired compound.

[0574] Scheme XII describes the preparation of 6-aminophthalazine intermediates.

[0575] Synthesis of 6-aminophthalazines in which the 1-position may be a protected amine could be accomplished starting from commercially available 2-bromo-5-nitrotoluene. Displacement of bromide with cyanide followed by bromination of tolyl methyl will give a benzyl bromide. Displacement of bromide with hydrazine would afford benzyl hydazine intermediate suitable for ring closure by subsequent addition to the nitrile under thermal conditions to yield the phthalazine core. Suitable protection and reduction of the aryl nitro group would provide the title compound.

[0576] The A—B moieties of the present can be prepared by methods known to those of skill in the art. The A—B moieties of the present can be prepared by methods described in the above-identified publications. For example, the following publications, the contents of which are incorporated herein by reference, describe and exemplify means of preparing A—B moieties: WO97/23212, WO97/30971, WO98/06694, WO98/01428, WO98/28269, and WO98/28282.

[0577] Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Example 1

3,5-Difluoro-4-dimethylamino-1-(2-aminomethylphenoxy)-6-((2′-sulfamido-[1,1′]-biphen-4-oxy))pyridine

[0578]

[0579] Synthesis of Compound (A)

[0580] To the solution of 4-(dimethylamino-2,3,5,6-tetrafluoropyridine (10.3 mmol, 2.0 g) in dimethylformamide (10 mL) was added the mixture of 2-cyanophenol (1.227g, 1.0 eq.) and potassium t-butoxide (1.156 g, 1.0 eq.) in dimethylformamide (15 mL) slowly. This reaction mixture was heated at 60° C. for 18 h. The reaction mixture was cooled to ambient temperature and to this mixture was added water (10 mL) to give precipitate, which was collected by filtration. This crude product was purified by flash chromatography on a silica gel column (5 g) eluted with 4:1 hexane:ethyl acetate to give 1.116 g of pure product (37%).

[0581] Synthesis of Compound (B)

[0582] A mixture of 3-bromophenol (0.01 mol, 1.73 g), boronic acid (2.57 g, 1.0 eq.), tetrakis(triphenylphosphine) palladium(O) (0.347 g, 0.03 eq.), and sodium carbonate (3.18 g, 3.0 eq.) in tetrahydrofuran (100 mL) and water (50 mL) was stirred at ambient temperature for 30 min. while nitrogen gas was bubbling to remove oxygen. This reaction mixture was then refluxed for 18 h. The reaction mixture was filtered through celite to remove catalyst and washed with tetrahydrofuran(50 mL). The filtrate was evaporated in vacuo and the residue was taken up in water then extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with brine, dried (MgSO4), and evaporated. This residue was purified by flash chromatography on a silica gel column(10 g) eluted with 2.5:1 hexane:ethyl acetate to give 2.508 g of pure product (82%).

[0583] Synthesis of Compound (C)

[0584] To the solution of (A) (3.8056 mmol, 1.116 g) in dimethylformamide (10 mL) was added the mixture of (B) (1.162 g, 1.0 eq.) and potassium t-butoxide (0.427 g, 1.0 eq.) in dimethylformamide(10 mL) slowly. This reaction mixture was heated at 60° C. for 18 h. The reaction mixture was cooled to ambient temperature and to this mixture was added water(10 mL) to give precipitate, which was collected by filtration. This crude product was purified by by HPLC on a C-18 column eluted with solvent mixture A (water:TFA 99.95:0.05) and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a gradient starting with A at 50% and changing to B at 100% over 50 min. After lyophylization, 0.35 g of pure product (16%) was obtained.

[0585] Synthesis of Compound (D)

[0586] To a solution of (C) (0.5703 mmol, 0.33 g) in methanol (10 mL) was added palladium hydroxide on carbon (0.066 g, 20 wt %), palladium on carbon from Fluka (0.033g, 10 wt %), and 2 drops of conc. hydrochloric acid. This reaction mixture was stirred under house vacuum for 10 minutes at ambient temperature to remove oxygen. Then subjected to 1 atm H2 via balloon method for 18 h. The reaction mixture was filtered through celite to remove catalyst and washed with methanol (10 mL). The filtrate was evaporated under vacuum. This residue was dissolved in 100% trifluoroacetic acid (5 mL) and this reaction mixture was heated at 55° C. for 2 h. After removing trifluoroacetic acid, the crude product was purified by HPLC on a C-18 column eluted with solvent mixture A (water:TFA 99.95:0.05) and solvent mixture B (acetonitrile:TFA 99.95:0.05) using a gradient starting with A at 80% and changing to B at 80% over 40 min. to give 0.15 g of pure product(50%); HRMS for C26H25F2N4O4S m/z (M+H)+ calc. 527.5751, found 527.1566.

[0587] Utility

[0588] The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term “thromboembolic disorders” as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa, thrombin, or both.

[0589] The effectiveness of compounds of the present invention as inhibitors of factor Xa can be determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) can be measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which can be monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki.

[0590] Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, Km, for substrate hydrolysis can be determined at 25° C. using the method of Lineweaver and Burk. Values of Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship can be used to calculate Ki values:

(vo−vs)/vs=I/(Ki(1+S/Km))

[0591] where:

[0592] vo is the velocity of the control in the absence of inhibitor;

[0593] vs is the velocity in the presence of inhibitor;

[0594] I is the concentration of inhibitor;

[0595] Ki is the dissociation constant of the enzyme:inhibitor complex;

[0596] S is the concentration of substrate;

[0597] Km is the Michaelis constant.

[0598] Compounds tested in the above assay are considered to be active if they exhibit a Ki of ≦10 μM. Preferred compounds of the present invention have Ki's of ≦1 μM. More preferred compounds of the present invention have Ki's of ≦0.1 μM. Even more preferred compounds of the present invention have Ki's of ≦0.01 μM. Still more preferred compounds of the present invention have Ki's of ≦0.001 μM.

[0599] The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

[0600] The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

[0601] Compounds of the present invention can be shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) can be monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, can be incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity can be assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk.

[0602] Compounds tested in the above assay are considered to be active if they exhibit a Ki of ≦10 μM. Preferred compounds of the present invention have Ki's of ≦1 μM. More preferred compounds of the present invention have Ki's of ≦0.1 μM. Even more preferred compounds of the present invention have Ki's of ≦0.01 μM. Still more preferred compounds of the present invention have Ki's of ≦0.001 μM.

[0603] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

[0604] The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

[0605] By “administered in combination” or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

[0606] The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

[0607] The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and EP 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in WO92/07869 and EP 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

[0608] The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

[0609] Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

[0610] The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

[0611] The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.

[0612] Dosage and Formulation

[0613] 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.

[0614] 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.

[0615] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0616] 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.

[0617] 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.

[0618] 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.

[0619] 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.

[0620] 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.

[0621] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[0622] 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.

[0623] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0624] 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.

[0625] Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0626] Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

[0627] Capsules

[0628] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

[0629] Soft Gelatin Capsules

[0630] A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

[0631] Tablets

[0632] Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

[0633] Injectable

[0634] A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

[0635] Suspension

[0636] An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

[0637] Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

[0638] Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

[0639] Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-800% when administered with a compound of Formula I.

[0640] Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

[0641] 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 Formula I 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 which effects 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.

[0642] 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.

[0643] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

	Number	Date	Country
Parent	09469831	Dec 1999	US
Child	10007195	Dec 2001	US

Thrombin or factor Xa inhibitors

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