Substituted amino methyl factor Xa inhibitors

The present application describes substituted-aminomethyl substituted compounds and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 3,365,459, 3,340,269, and 3,423,414 illustrate anti-inflammatory inhibitors of the following formula:
wherein A is 2-3 carbon atoms, X can be O, and R1and R3can be substituted or unsubstituted aromatic groups. None of these patents, however, exemplify or suggest compounds of the present invention.

U.S. Pat. No. 5,342,851 depicts thiazole platelet aggregation inhibitors including those of the following formula:
wherein A is a linker, B can be a linker or a ring, Q is a ring or an amino group, R, R1, and R3are a variety of groups. This patent, however, does not exemplify or suggest compounds of the present invention.

WO00/39131 describes heterobicyclic Factor Xa inhibitors of which the following is an example formula:
wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclic moiety and B is a basic group or a cyclic moiety. Compounds specifically described in WO00/39131 are not considered to be part of the present invention.

WO98/28269, WO98/28282, WO99/32454, U.S. Pat. No. 6,020,357, and U.S. Pat No. 6,271,237 describe Factor Xa inhibitors of the following formula:
wherein ring M is a heterocycle, Z is a linker, A is a ring, B is a basic or cylic group, D is a basic moiety, and E is a ring. Compounds specifically described in WO098/28269, WO98/28282, WO99/32454, U.S. Pat. Nos. 6,020,357, and U.S. Pat. No. 6,271,237 are not considered to be part of the present invention.

WO98/57951 describes Factor Xa inhibitors of the following formula:
wherein ring M can be a variety of heterocycles and rings D-E represent a heterobicyclic group. Compounds specifically described in WO98/57951 are not considered to be part of the present invention.

WO98/57934 and U.S. Pat. No. 6,060,491 describe Factor Xa inhibitors of the following formula:
wherein ring M is a 6-membered heteroaryl, Z is a linker, A is a ring, B is a basic or cylic group, D is a basic moiety, and E is a ring. Compounds specifically described in WO98/57934 and U.S. Pat. No. 6,060,491 are not considered to be part of the present invention.

WO98/57937 and U.S. Pat. No. 5,998,424 describe Factor Xa inhibitors of the following formula:
wherein ring M is a variety of rings, ring D is an aromatic ring, and R and E are non-basic groups. Compounds specifically described in WO98/57937 and U.S. Pat. No. 5,998,424 are not considered to be part of the present invention.

WO99/50255 and U.S. Pat. No. 6,191,159 describe pyrazoline and triazoline Factor Xa inhibitors of the following formulas:
Compounds specifically described in WO99/50255 and U.S. Pat. No. 6,191,159 are not considered to be part of the present invention.

WO00/59902 describes Factor Xa inhibitors of the following formula:
wherein ring M can be a variety of rings all of which are substituted with Z-A-B, Z is a linker, A is a ring, B is a sulfonyl-containing heterobicycle, and rings D-E represent a heterobicyclic group or a 6-membered ring. Compounds specifically described in WO00/59902 are not considered to be part of the present invention.

WO01/32628 describes cyano-pyrroles, cyano-imidazoles, cyano-pyrazoles, and cyano-triazoles that are Factor Xa inhibitors. Compounds specifically described in WO01/32628 are not considered to be part of the present invention.

WO01/05784 describes Factor Xa inhibitors of the following formulas:
wherein Z is C or N, G is a mono- or bicyclic ring M, A is a linker, B is a basic or cyclic group. Compounds specifically described in WO01/05784 are not considered to be part of the present invention.

WO00/39108 describes Factor Xa inhibitors of the following formula:
wherein ring M can be a variety of heterocycles and rings D-E represent a heterobicyclic group. Compounds specifically described in WO00/39108 are not considered to be part of the present invention.

WO01/19798 describes factor Xa inhibitors of the following formula:
A-Q-D-E-G-J-X
wherein A, D, G, and X can be phenyl or heterocycle. However, none of the presently claimed compounds are exemplified or suggested in WO01/19798.

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.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors. In addition, it is also desirable to find new compounds with improved pharmacological characteristics compared with known factor Xa inhibitors. For example, it is preferred to find new compounds with improved factor Xa inhibitory activity and selectivity for factor Xa versus other serine proteases (i.e., trypsin). It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages and/or once-daily dosing); (c) factors which decrease blood concentration peak-to-trough characteristics (e.g., clearance and/or volume of distribution); (d) factors that increase the concentration of active drug at the receptor (e.g., protein binding, volume of distribution); (e) factors that decrease the liability for clinical drug-drug interactions (e.g., cytochrome P450 enzyme inhibition or induction); (f) factors that decrease the potential for adverse side-effects (e.g., pharmacological selectivity beyond serine proteases, potential chemical or metabolic reactivity, and limited CNS penetration); and, (g) factors that improve manufacturing costs or feasibility (e.g., difficulty of synthesis, number of chiral centers, chemical stability, and ease of handling).

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel substituted-aminomethyl substituted compounds that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

The present invention provides 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.

The present invention provides 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.

The present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.

The present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.

The present invention provides novel compounds for use in therapy.

The present invention provides the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.

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

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] In an embodiment, the present invention provides a novel compound of formula I:
P4—P-M-M4Ior a stereoisomer or pharmaceutically acceptable salt thereof, wherein;M is a 3-10 membered carbocycle or a 4-10 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from O, S(O)p, N, and NZ2;ring M is substituted with 0-3 R1aand 0-2 carbonyl groups, and there are 0-3 ring double bonds;P is fused onto ring M and is a 5, 6, or 7 membered carbocycle or a 5, 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from O, S(O)p, and N;ring P is substituted with 0-3 R1aand 0-2 carbonyl groups, and there are 0-3 ring double bonds;alternatively, ring P is absent and P4is directly attached to ring M;one of P4and M4is -Z-A-B and the other -G1-G, provided that P4and M4are attached to different rings when ring P is present;G is a group of formula IIa or IIb:ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p;ring D is substituted with 0-2 R and there are 0-3 ring double bonds;E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1-2 R;alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5-6 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and has 0-3 ring double bonds;R is selected from H, C1-4alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, CN, C(═NR8)NR7R9, NHC(═NR8)NR7R9, ONHC(═NR8)NR7R9, NR8CH(═NR7), NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3alkyl), CH2N(C1-3alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3alkyl), CH2CH2N(C1-3alkyl)2, (CR8R9)tC(O)H, (CR8R9)tC(O)R2c, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, (CR8R9)tNR7C(O)R7, (CR8R9)tOR3, (CR8R9)tS(O)pNR7R8, (CR8R9)tNR7S(O)pR7, (CR8R9)tSR3, (CR8R9)tS(O)R3, (CR8R9)tS(O)2R3, and OCF3;alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;A is selected from:

5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 1 R4aand 0-2 R4;G1is absent or is selected from (CR3R3a)1-5, (CR3R3a)0-2CR3═CR3(CR3R3a)0-2, (CR3R3a)0-2C≡C(CR3R3a)0-2, (CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uC(O)O(CR3R3a)w, (CR3R3a)uOC(O)(CR3R3a)w, (CR3R3a)uO(CR3R3a)w, (CR3R3a)uN3b(CR3R3a)w, (CR3R3a)uC(O)N3b(CR3R3a)w, (CR3R3a)uN3bC(O)(CR3R3a)w, (CR3R3a)uOC(O)N3b(CR3R3a)w, (CR3R3a)uN3bC(O)O(CR3R3a)w, (CR3R3a)uN3bC(O)N3b(CR3R3a)w, (CR3R3a)uN3bC(S)N3b(CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(O)(CR3R3a)w, (CR3R3a)uS(O)2(CR3R3a)w, (CR3R3a)uS(O)N3b(CR3R3a)w, (CR3R3a)uN3bS(O)2(CR3R3a)w, (CR3R3a)uS(O)2N3b(CR3R3a)w, (CR3R3a)uN3bS(O)2N3b(CR3R3a)w, (CR3R3a)uNR3e(CR3R3a)w, (CR3R3a)uC(O)(CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uNR3b(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uC(O)(CR3R3a)uC(O)NR3b(CR3R3a), (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uS(O)NR3bC(O)(CR3R3a)w, (CR3R3a)uC(O)NR3bS(O)2(CR3R3a)w, and (CR3R3a)uS(O)2NR3bC(O)NR3bCR3R3a)w, wherein u+w total 0, 1, 2, 3, or 4, provided that G1does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;Z is selected from a bond, —(CR3R3e)1-4—, (CR3R3e)qO(CR3R3e)q1, (CR3R3e)qNR3b(CR3R3e)q1, (CR3R3e)qC(O)(CR3R3e)q1, (CR3R3e)qC(O)O(CR3R3e)q1, (CR3R3e)qOC(O)(CR3R3e)q1, (CR3R3e)qC(O)NR3b(CR3R3e)q1, (CR3R3e)qNR3bC(O)(CR3R3e)q1, (CR3R3e)qOC(O)O(CR3R3e)q1, (CR3R3e)qOC(O)NR3b(CR3R3e)q1, (CR3R3e)qNR3bC(O)O(CR3R3e)q1, (CR3R3e)qNR3bC(O)NR3b(CR3R3e)q1, (CR3R3e)qC(O)(CR3R3e)qC(O)(CR3R3e)q1, (CR3R3e)qNR3b(CR3R3e)qC(O)NR3b(CR3R3e)q1, (CR3R3e)qNR3bC(O)(CR3R3e)qC(O)(CR3R3e)q1, (CR3R3e)qC(O)(CR3R3e)qC(O)NR3b(CR3R3e)q1, (CR3R3e)qNR3bC(O)(CR3R3e)qC(O)NR3b(CR3R3e)q1, (CR3R3e)qS(CR3R3e)q1, (CR3R3e)qS(O)(CR3R3e)q1, (CR3R3e)qS(O)2(CR3R3e)q1, (CR3R3e)qSO2NR3b(CR3R3e)q1, (CR3R3e)qNR3bSO2(CR3R3e)q1, (CR3R3e)qS(O)NR3bC(O)(CR3R3e)q1, (CR3R3e)qC(O)NR3bS(O)2(CR3R3e)q1, and (CR3R3e)qNR3bSO2NR3b(CR3R3e)q1, wherein q+q1 total 0, 1, 2, 3, or 4, provided that Z does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;Z2is selected from H, S(O)2NHR3b, C(O)R3b, C(O)NHR3b, C(O)OR3f, S(O)R3f, S(O)2R3f, C1-6alkyl substituted with 0-2 R1a, C2-6alkenyl substituted with 0-2 R1a, C2-6alkynyl substituted with 0-2 R1a, —(C0-4alkyl)-cycloalkyl substituted with 0-3 R1a, —(C0-4alkyl)-heterocycle substituted with 0-3 R1a, —(C0-4alkyl)-aryl substituted with 0-3 R1a, and, —(C0-4alkyl)-heteroaryl substituted with 0-3 R1a;R1a, at each occurrence, is selected from H, —(CR3R3a)r—R1b, —(CR3R3a)r—CR3R1bR1b, —(CR3R3a)r—O—(CR3R3a)r—R1b, —(CR3R3a)r—NR2—(CR3R3a)r—R1b, —(CR3R3a)r—S(O)p—(CR3R3a)r—R1b, —(CR3R3a)r—CO2—(CR3R3a)r—R1b, —(CR3R3a)r—C(O)NR2—(CR3R3a)r—R1b, —(CR3R3a)r—C(O)—(CR3R3a)r—R1b, —C2-6alkenylene-R1b, —C2-6alkynylene-R1b, and —(CR3R3a)r—C(═NR1b)NR3R1b, provided that R1aforms other than an N-halo, N—S, O—O, or N—CN bond;alternatively, when two R1agroups are attached to adjacent atoms or to the same carbon atom, together with the atoms to which they are attached, they form a 5-7 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, this ring being substituted with 0-2 R4band comprising: 0-3 double bonds;R1bis selected from H, C1-3alkyl, F, Cl, Br, I, —CN, —NO2, —CHO, (CF2)rCF3, (CR3R3a)rOR2, NR2R2a, C(O)R2b, CO2R2b, OC(O)R2, CH(CH2OR2)2, (CF2)rCO2R2a, S(O)pR2b, NR2(CH2)rOR2, C(═NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NR2R2a, NR2C(O)2R2a, OC(O)NR2R2a, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2, C(O)NR2SO2R2, C3-6carbocycle substituted with 0-2 R4b, and 5-10 membered heterocycle substituted with 0-2 R4band consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R1bforms other than an O—O, N-halo, N—S, or N—CN bond and provided that S(O)pR2forms other than S(O)2H or S(O)H;R2, at each occurrence, is selected from H, CF3, C1-6alkyl, benzyl, —(CH2)r—C3-10carbocycle substituted with 0-2 R4b, and —(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4b;R2a, at each occurrence, is selected from H, CF3, C1-6alkyl, benzyl, —(CH2)r—C3-10carbocycle substituted with 0-2 R4b, and —(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4b;alternatively, R2and 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 R4band consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;R2b, at each occurrence, is selected from CF3, C1-4alkoxy, C1-6alkyl substituted with 0-2 R4b, —(CH2)r—C3-10carbocycle substituted with 0-2 R4b, and —(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4b;R2c, at each occurrence, is selected from CF3, OH, C1-4alkoxy, C1-6alkyl, —(CH2)r—C3-10carbocycle substituted with 0-2 R4b, and —(CH2)r-5-10 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4b;R2d, at each occurrence, is selected from H, R4c, C1-6alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-10carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4c, provided that R2dforms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N,—S(O)pS(O)p, S—O, O—N, O—S, or O—O moiety;R2e, at each occurrence, is selected from H, R4c, C1-6alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-10carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4c, provided that R2eforms other than a C(O)-halo or C(O)—S(O)pmoiety;R3, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;R3a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;alternatively, R3and R3a, together with the nitrogen atom to which they are attached, combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R3and R3aare attached, and 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;R3b, at each occurrence, is selected from CF3, C1-4alkoxy substituted with 0-2 R4b, C1-6alkyl substituted with 0-2 R4b, —(CH2)r—C3-10carbocycle substituted with 0-2 R4b, and —(CH2)r-5-10 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4b;R3c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C1-4alkyl-phenyl, and C(═O)R3c;R3e, at each occurrence, is selected from H, SO2NHR3, SO2NR3R3, C(O)R3, C(O)NHR3, C(O)OR3f, S(O)R3f, S(O)2R3f, C1-6alkyl substituted with 0-2 R1a, C2-6alkenyl substituted with 0-2 R1a, C2-6alkynyl substituted with 0-2 R1a, —(C0-4alkyl)-5-10 membered carbocycle substituted with 0-3 R1a, and —(C0-4alkyl)-5-10 membered heterocycle substituted with 0-3 R1aand consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;R3f, at each occurrence, is selected from: C1-6alkyl substituted with 0-2 R1a, C2-6alkenyl substituted with 0-2 R1a, C2-6alkynyl substituted with 0-2 R1a, —(C0-4alkyl)-5-10 membered carbocycle substituted with 0-3 R1a, and —(C0-4alkyl)-5-10 membered heterocycle substituted with 0-3 R1aand consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;R3g, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —(CH2)r-3-6 membered carbocycle, and —(CH2)r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;alternatively, when R3and R3gare attached to the same carbon atom, they combine with the attached carbon atom to form a cyclopropyl group;R4, at each occurrence, is selected from H, ═O, (CR3R3a)rOR2, F, Cl, Br, I, C1-4alkyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (CR3R3a)rC(O)R2c, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rC(═NR2)NR2R2a, (CR3R3a)rC(═NS(O)2R5a)NR2R2a, (CR3R3a)rNHC(═NR2)NR2R2a, (CR3R3a)rC(O)NHC(═NR2)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rNR2SO2—C1-4alkyl, (CR3R3a)rNR2SO2R5a, (CR3R3a)rS(O)pR5a, (CR3R3a)r(CF2)rCF3, NHCH2R1b, OCH2R1b, SCH2R1b, N(CH2)2(CH2)tR1b, O(CH2)2(CH2)tR1b, S(CH2)2(CH2)tR1b, (CR3R3a)r-5-6 membered carbocycle substituted with 0-1 R5, and a (CR3R3a)r-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-1 R5;R4ais selected from (CR3R3g)rN(→O)R2dR2d, (CR3R3g)v—NR2dC(O)R2e, (CR3R3g)v—C(O)NR2dR2d, (CR3R3g)v—NR2dC(O)NR2dR2d, (CR3R3g)v—NR2dC(O)OR2d, (CR3R3g)v—SO2NR2dR2d, (CR3R3g)v—NR2dSO2NR2dR2d, (CR3R3g)v—C(O)NR2dSO2R2d, (CR3R3g)v—NR2dSO2R2d, and (CR3R3g)v—S(O)pR2d, provided that S(O)pR2dforms other than S(O)2H or S(O)H;alternatively, R4ais selected from (CR3R3g)rNR2dR2d, NR2dC(O)R2e, C(O)NR2dR2d, NR2dC(O)NR2dR2d, NR2dC(O)OR2d, SO2NR2dR2d, NR2dSO2NR2dR2d, C(O)NR2dSO2R2d, NR2dSO2R2d, and S(O)pR2d, provided that at least one of R2dand R2eis alkyl substituted with at least one R4cthat is other than alkyl, provided that S(O)pR2dforms other than S(O)2H or S(O)H;R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4alkyl, (CH2)rCN, (CH2)rNO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, (CH2)rNR3C(O)R3a, (CH2)r—C(O)NR3R3a, (CH2)rNR3C(O)NR3R3a, (CH2)r—C(═NR3)NR3R3a, (CH2)rNR3C(═NR3)NR3R3a, (CH2)rSO2NR3R3a, (CH2)rNR3SO2NR3R3a, (CH2)rNR3SO2—C1-4alkyl, (CH2)rNR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4alkyl, (CH2)rS(O)p-phenyl, and (CH2)r(CF2)rCF3;R4c, at each occurrence, is selected from ═O, (CR3R3a)rOR2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a)rCF3, C1-4alkyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (CR3R3a)rN(→O)R2R2a, (CR3R3a)rC(O)R2c, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a, (CR3R3a)rN═CHOR3, (CR3R3a)rC(O)NH(CH2)2NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rC(═NR2)NR2R2a, (CR3R3a)rNHC(═NR2)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rC(O)NHSO2—C1-4alkyl, (CR3R3a)rNR2SO2R5a, (CR3R3a)rS(O)pR5a, (CF2)rCF3, (CR3R3a)rC3-10carbocycle substituted with 0-2 R4b, and (CR3R3a)r5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)pand substituted with 0-2 R4b;R5, at each occurrence, is selected from H, C1-6alkyl, ═O, (CH2)rOR3, F, Cl, Br, I, —CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, (CH2)rNR3C(O)R3a, (CH2)rC(O)NR3R3a, (CH2)rNR3C(O)NR3R3a, (CH2)rCH(═NOR3d), (CH2)rC(═NR3)NR3R3a, (CH2)rNR3C(═NR3)NR3R3a, (CH2)rSO2NR3R3a, (CH2)rNR3SO2NR3R3a, (CH2)rNR3SO2—C1-4alkyl, (CH2)rNR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4alkyl, (CH2)rS(O)p-phenyl, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;R5a, at each occurrence, is selected from C1-6alkyl, (CH2)rOR3, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, (CH2)rNR3C(O)R3a, (CH2)rC(O)NR3R3a, (CF2)rCF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6, provided that R5adoes not form a S—N or S(O)p—C(O) bond;R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo C1-4alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2—C1-4alkyl;R7, at each occurrence, is selected from H, OH, C1-6alkyl, C1-6alkyl-C(O)—, C1-6alkyl-O—, (CH2)n-phenyl, C1-4alkyl-OC(O)—, C6-10aryl-O—, C6-10aryl-OC(O)—, C6-10aryl-CH2—C(O)—, C1-4alkyl-C(O)O—C1-4alkyl-OC(O)—, C6-10aryl-C(O)O—C1-4alkyl-OC(O)—, C1-6alkyl-NH2—C(O)—, phenyl-NH2—C(O)—, and phenyl C1-4alkyl-C(O)—;R8, at each occurrence, is selected from H, C1-6alkyl, and (CH2)n-phenyl;alternatively, R7and R8, when attached to the same nitrogen, combine to form a 5-10 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p;R9, at each occurrence, is selected from H, C1-6alkyl, and (CH2)n-phenyl;n, at each occurrence, is selected from 0, 1, 2, and 3;p, at each occurrence, is selected from 0, 1, and 2;r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;t, at each occurrence, is selected from 0, 1, 2, and 3;v, at each, occurrence, is selected from 1, 2, 3, 4, 5, and 6; and,provided that when ring M is phenyl and is substituted 1,2 by M4and P4and G1is present, then Z-A is other than NHC(O)-thienyl, NHCH2-thienyl, NHC(O)-benzothienyl, and NHCH2-benzothienyl;further provided that when (a) P is absent, (b) ring M is a non-aromatic ring with at least one ring N, (c) G-G1is attached via a ring N, and (d) Z is at least two atoms in length, then Y is other than phenyl or pyridyl.
[2] In a preferred embodiment, the present invention provides a novel compound of Formula II:or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;ring M, including P1, P2, M1, and M2, is a 5, 6, or 7 membered carbocycle or a 5, 6, or 7 membered heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from O, S(O)p, N, and NZ2;ring M is substituted with 0-2 R1aand 0-2 carbonyl groups, and there are 0-3 ring double bonds;ring P, including P1, P2, and P3, is a 5 or 6 membered aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from O, S(O)p, and N;alternatively, ring P, including P1, P2, and P3, is a 5 or 6 membered dihydro-aromatic heterocycle, consisting of: carbon atoms and 1-3 heteroatoms selected from O, S(O)p, and N;ring P is substituted with 0-2 R1a; one of P4and M4is -Z-A-B and the other -G1-G;G is a group of formula IIa or IIb:ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p;ring D is substituted with 0-2 R and there are 0-3 ring double bonds;E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2 R;alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 1 R and with a 5 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and there are 0-3 ring double bonds;R is selected from H, C1-4alkyl, F, Cl, OH, OCH3, OCH2CH3, OCH(CH3)2, CN, C(═NH)NH2, C(═NH)NHOH, C(═NH)NHOCH3, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3alkyl), CH2N(C1-3alkyl)2, (CR8R9)tNR7R8, C(O)NR7R8, CH2C(O)NR7R8, S(O)2R3, S(O)pNR7R8, CH2S(O)pNR7R8, and OCF3;alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;A is selected from:

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

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

In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.

In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.

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

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

In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is compound of the present invention or a pharmaceutically acceptable salt thereof and the second therapeutic agent is at least one agent selected from a second factor Xa inhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent.

In another preferred embodiment, the present invention provides a novel method, wherein the second therapeutic agent is at least one anti-platelet agent.

In another preferred embodiment, the present invention provides a novel method, wherein the anti-platelet agent is aspirin and clopidogrel.

In another preferred embodiment, the present invention provides a novel method, wherein the anti-platelet agent is clopidogrel.

In another embodiment, the present invention provides a novel article of manufacture, comprising:

(a) a first container;

(b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,

(c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising:

(d) a second container;

wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article of manufacture, comprising:

(a) a first container;

(b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,

(c) a package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising:

(d) a second container;

wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.

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

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

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

Definitions

Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole. Preferably, the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.

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 R6groups and R6at 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.

In cases wherein there are amines on the compounds of this invention, these can be converted to amine N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed amines are considered to cover both the shown amine and its N-oxide (N→O) derivative.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-6alkyl, is intended to include C1, C2, C3, C4, C5, and C6alkyl 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 —CvFwwhere 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. C1-6alkoxy, is intended to include C1, C2, C3, C4, C5, and C6alkoxy 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. C3-7cycloalkyl is intended to include C3,4, C5, C6, and C7cycloalkyl groups. Alkenyl” is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl. C2-6alkenyl is intended to include C2, C3, C3, C5, and C6alkenyl groups. “Alkynyl” is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C2-6Alkynyl is intended to include C2, C3, C4, C5, and C6alkynyl groups.

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

As used herein, “carbocycle” or “carbocyclic residue” 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 ring, any of which may be saturated, partially unsaturated, or unsaturated (aromatic). Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a trycyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

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 ring heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 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, O and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a trycyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. “Prodrugs” are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that there presently recited compounds do not contain a N-halo, S(O)2H, or S(O)H group.

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

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

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

Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

The compounds of the present invention of formula I (Scheme 1) where P is not fused onto ring M could be prepared as outlined in Scheme 2 to Scheme 8 and via standard methods known to those skilled in the art.

The compounds of the present invention of formula I where B is imidazole can be prepared as shown in Scheme 2. Commercially available imidazole 2-carboxaldehyde can be used as the starting material. Reductive amination, followed by protection of the amino group can produce the imidazole intermediate 2. Ullman coupling of imidazole 2 with iodide 3 can give the biaryl A-B precursor 4, which can be coupled with 5 using standard coupling conditions to provide 6. Deprotection of the CBZ group, followed by reaction with acid chlorides, carbamoyl chloride, sulfonyl chlorides, and isocyanates can provide compounds of the invention with structures 7, 8, 9, and 10. Similarly, other compounds of the present invention where B is an imidazole derivative could be prepared as shown in Scheme 3 using 2-aminomethylimidazole (JOC, 43 (8), 1978, 1603) as the starting material.

Compounds of formula I where B is a phenyl derivative can be prepared as shown in Scheme 4. Suzuki coupling of iodide 19 with boric acid 20 can afford the biaryl intermediate 21, which can be coupled with 5 through standard coupling conditions to give 22. Reductive amination, followed by reactions with acid chlorides, carbamates, sulfonyl chlorides, and isocyanates can provide compounds of this invention having structures 23-26.

Aminopyridyl and aminopyrimidyl A-B analogs (see structures in Scheme 5) can be prepared using routes similar to those of Scheme 4.

Additional Z-linkers to the A-B intermediates can be synthesized by the chemical manipulation of the amino functionality (Scheme 6) of the compounds described above.

Other possible A-B intermediates with various Z-linkers can be synthesized by the methods shown in Scheme 7. The iodo-ester intermediate can be subjected to Ullman and/or Suzuki coupling methodologies to afford A-B intermediates. These intermediates in turn can be homologated via the Arndt Eistert methodology to afford other A-B intermediates. Alternatively, the ester functionality can be reduced to the alcohol that in turn can be converted to a variety of A-B intermediates by procedures known to those skilled in the art.

Non-aromatic intermediates as shown in Scheme 8 can be synthesized via procedures known to those skilled in the art. These intermediates can than be further manipulated to incorporate R4avia procedures previously described.

The compounds of formula I (Scheme 1) where P is fused onto ring M can be prepared as outlined in Schemes 9 to 11 and via standard methods known to those skilled in the art. The halogenated intermediates illustrated in these Schemes can be subjected to the Ullman or the Suzuki coupling methodologies to afford the intermediates shown. Further elaboration of these intermediates using the methods described above and by those skilled in the art should provide compounds of the present invention.

The compounds of this invention and the intermediates described above wherein the B group contains an oxidizable group can be oxidized, e.g. N to N-oxide.

Schemes 2-11 describe how to make the A-B moieties of the present invention and how to couple them to prepare compounds of the present invention. In the above Schemes, the Z group may or may not be present depending on how the A-B group is coupled. The coupling portion of the A-B group could (a) be displaced by the incoming Z or M group, (b) become the Z group, or (c) be incorporated into ring M.

The remaining portions of the compounds of the present invention, G-G1-P-M-Z, G-G1-M-P-Z, G-G1-P-M, G-G1-M-P, G-G1-M-Z, and G-G1-M, can be prepared using methods known to those of ordinary skill in the art. All of the following patents and publications are incorporated herein by reference. For compounds wherein ring P is absent and ring M is a 5-, 6-, or 7-membered ring, one of ordinary skill in the art can look to U.S. Pat. Nos. 5,939,418, 5,925,635, 6,057,342, 6,187,797, 6,020,357, 6,060,491, 5,998,424, 6,191,159, WO98/57951, WO99/32454, WO00/039108, WO00/059902, WO01/32628, WO01/005785, U.S. Ser. Nos. 09/892,319, U.S. Ser. Nos. 60/313,552, 60/246,108, and U.S. Ser. No. 09/887,936 for starting materials and intermediates to which the present B and/or A-B groups can be coupled. For compounds wherein ring P is fused to ring M (i.e., a bicyclic moiety is present), one of ordinary skill in the art can look to WO00/39131, U.S. Ser. Nos. 60/246,125, 60/292,665, 60/278,173, 60/278,165, and U.S. Ser. No. 09/887,850 for starting materials and intermediates to which the present B and/or A-B groups can be coupled.

For compounds wherein G is a ring substituted with a basic moiety, one of ordinary skill in the art can look to U.S. Pat. Nos. 5,939,418, 5,925,635, 6,057,342, 6,187,797, 6,020,357, 6,060,491, 6,191,159, WO98/57951, WO99/32454, WO00/059902, WO01/32628, WO00/39131, U.S. Ser. No. 09/892,319, U.S. Ser. Nos. 60/313,552, 60/246,108, 60/246,125, 60/292,665, 60/278,173, and U.S. Ser. No. 60/278,165 for starting materials and intermediates to form the present G-G1-P-M-Z, G-G1-M-P-Z, G-G1-P-M-Z-A, and/or G-G1-M-P-Z-A groups to which the present B and/or A-B groups can be coupled. For compounds wherein G is a ring substituted with a non-basic group, one of ordinary skill in the art can look to U.S. Pat. No. 5,998,424, WO00/39131, WO00/059902, WO01/32628, U.S. Ser. Nos. 09/892,319, 60/313,552, U.S. Ser. Nos. 60/246,108, 60/246,125, 60/292,665, 60/278,173, and U.S. Ser. No. 60/278,165 for starting materials and intermediates to form the present G-G1-P-M-Z, G-G1-P-Z, G-G1-P-M-Z-A, and/or G-G1-M-P-Z-A groups to which the present B and/or A-B groups can be coupled. For compounds wherein G is a bicyclic moiety, one of ordinary skill in the art can look to WO98/57951, WO00/039108, WO00/39131, U.S. Ser. No. 09/892,319, U.S. Ser. Nos. 60/313,552, 60/246,108, 60/246,125, 60/292,665, 60/278,173, and U.S. Ser. No. 60/278,165 for starting materials and intermediates to form the present G-G1-P-M-Z, G-G1-M-P-Z, G-G1-P-M-Z-A, and/or G-G1-M-P-Z-A groups to which the present B and/or A-B groups can be coupled. For compounds wherein A is an indoline or similar bicycle, one of ordinary skill in the art can look to WO01/005785 for starting materials and intermediates to which the present B group can be coupled or from which the present A-B groups can be formed. Scheme 12 illustrates some of the numerous pyrrole intermediates that can be used to prepare compounds of the present invention (RZis the point of attachment for Z-A-B and can be H, a protecting group, a group modifiable to Z or Z-A, Z, Z-A, or A). These intermediates are described in the above-noted patents and publications.

Scheme 13 illustrates some of the numerous imidazole, triazole, and tetrazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. In Scheme 13, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide. In Scheme 13, U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide.

Scheme 14 shows some of the numerous pyrazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications.

Scheme 15 depicts some of the numerous oxazole, thiazole, isoxazole, oxadiazole, and thiadiazole intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. In Scheme 15, V is nitro, amino, ester, or acid.

Scheme 16 illustrates two intermediates useful for making a compound of the present invention wherein ring P is fused to ring M. Scheme 16 also illustrates a number of bicyclic compounds that can be made from these intermediates or derivatives thereof. These intermediates and their modification are described in the above-noted patents and publications.

Scheme 17 depicts another intermediate useful for making a compound of the present invention wherein ring P is fused to ring M. Scheme 17 also illustrates a number of bicyclic compounds that can be made from this intermediate or derivatives thereof (e.g., the corresponding cyclohexenone). In Scheme 17, U is OH or morpholine and V is H or C(O)R1a. This intermediate, derivatives thereof, and their modification are described in the above-noted patents and publications.

Scheme 18 shows another intermediate useful for making a compound of the present invention wherein ring P is fused to ring M. Scheme 18 also illustrates a number of bicyclic compounds that can be made from this intermediate or derivatives thereof. This intermediate, derivatives thereof, and their modification are described in the above-noted patents and publications.

Scheme 19 illustrates a number of other bicyclic rings that are considered to be part of the present bicyclic group, rings P-M. Scheme 19 also describes a method of converting the shown rings to compounds of the present invention. As one of ordinary skill in the art would recognize, this method would be applicable to other heterobicyclics not shown.

Other useful pyrazole intermediates wherein G1is an amide are exemplified in Scheme 20. Compounds of the present invention wherein the G1group is other than an amide can be easily manipulated to other linker functionalities according to the methodologies known in the art, including the methodologies outlined in WO98/28269 and WO98/28282, the contents of both are incorporated herein by reference.

Scheme 21 depicts some of the numerous 6-membered aromatic ring intermediates that can be used to prepare compounds of the present invention. These intermediates are described in the above-noted patents and publications. In Scheme 21, V is nitro, protected sulfonamide, or ester group and is a precursor of group Z of the present invention.

Benzo fused dihydro-pyridone intermediates of the present invention can be prepared from readily available starting materials as shown in Scheme 22.

Other benzo-bicyclics can also be obtained as shown in Schemes 23 and 24.

When M is a non-aromatic ring, the compounds of this invention with general structure of Formula I can be synthesized by using similar methods as described previously and by those skilled in the art. One diastereomer of a compound of Formula I may display better activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.

When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Wilen, S. H.Tables of Resolving Agents and Optical Resolutions1972, 308 pp or using enantiomerically pure acids and bases. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen, E.Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- and diastereo-selective reactions and reagents known to one skilled in the art of asymmetric synthesis.

Utility

The compounds of this invention are inhibitors of factor Xa and are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals (i.e., factor Xa-associated disorders). In general, a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation). The term “thromboembolic disorders” as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart. The term “thromboembolic disorders” as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (e.g. after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty). The thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, atrial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

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

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 was determined at 25° C. using the method of Lineweaver and Burk. Values of Kiwere determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Kivalues:
(vo−vs)/vs=I/(Ki(1+S/Km))
where:vois the velocity of the control in the absence of inhibitor;vsis the velocity in the presence of inhibitor;I is the concentration of inhibitor;Kiis the dissociation constant of the enzyme:inhibitor complex;S is the concentration of substrate;Kmis the Michaelis constant.

Compounds tested in the above assay are considered to be active if they exhibit a Kiof ≦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. Using the methodology described above, a number of compounds of the present invention were found to exhibit Ki's of ≦10 μM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing that contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

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

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

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 the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat a thromboembolic condition or disease.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By “administered in combination” or “combination therapy” it is meant that a compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin (either unfractionated heparin or any commercially available low molecular weight heparin), synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and argatrobanas well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function, for example by inhibiting the aggregation, adhesion or granular secretion of platelets. 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, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) and piroxicam are preferred. Other suitable platelet inhibitory agents include IIb/IIIa antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g., dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y1and P2Y12, with P2Y12being even more preferred. Preferred P2Y12receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use.

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, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.

The term thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, denote agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Examples of suitable anti-arrythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class II agents (such as carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+channel openers such as IAchinhibitors, and IKurinhibitors (e.g., compounds such as those disclosed in WO01/40231).

Examples of suitable calcium channel blockers (L-type or T-type) for use in combination with the compounds of the present invention include diltiazem, verapamil, nifedipine, amlodipine and mybefradil.

Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.

Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include sprionolactone and eplirinone.

Examples of suitable phospodiesterase inhibitors for use in combination with the compounds of the present invention include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414).

Examples of suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.

Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.

Examples of suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol.

Examples of suitable anti-coagulants for use in combination with the compounds of the present invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin).

Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibitors (such as those disclosed in WO00/59506).

Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Examples of suitable anti-ulcer and gastroesophageal reflux disease agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.

Administration of the compounds of the present invention (i.e., a first therapeutic agent) in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent), preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each (i.e., a synergistic combination). A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. It is preferred that at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses. Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated. Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone.

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

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

Compounds of the present invention may further be useful as diagnostic agents and adjuncts. For example, the present compounds may be useful in maintaining whole and fractionated blood in the fluid phase such as required for analytical and biological testing.

The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic disorder (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat a thromboembolic disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping; and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been-formed (e.g., printed or applied).

Dosage and Formulation

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

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

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

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

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

Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, a standard reference text in this field.

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

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

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

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

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are afforded for illustration of the invention and are not intended to be limiting thereof.

Part A: Preparation of 6-[4-Iodophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

Part B: Preparation of 1-(4-iodophenyl)-3-(4-morpholinyl)-5,6-dihydro-2(1H)-pyridinone

Part C: Preparation of 1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione

4-Dimethylaminopyridine (3.92 g, 32.01 mmol) was dissolved into CH2Cl2(130 mL) and cooled to 0° C. Trifluoroacetic anhydride (4.54 g, 32.01 mmol) was added and the mixture was stirred at 0° C. for 30 min. A solution of the above morpholine-enamine from part B (10.25 g, 26.68 mmol) in CH2Cl2(370 mL) was added slowly. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated and purified by silica gel chromatography using 0%-50% ethyl acetate/hexane gradient to isolate the intermediate. The intermediate was dissolved in 20% HCl (50 mL) and diethyl ether (200 mL) and stirred at room temperature overnight. It was then quenched with water, extracted with ether (3×100 mL), washed with brine (1×100 mL), and dried (Na2SO4). The residue was re-dissolved in petroleum ether and the undissolved solid was filtered off. The filtrate was concentrated to afford 9.99 g of the desired product (78%).1HNMR (CDCl3) δ 7.77 (d, 2H), 7.11 (d, 2H), 3.93 (t, 2H), 2.92 (t, 2H) ppm.

Part D: Preparation of 1-[4-methoxyphenyl]-3-trifluoromethyl-6-[4-iodophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

Part E: Preparation of benzyl 1H-imidazol-2-yl-methyl-(methyl)carbamate

2-Imidazolecarboxyaldehyde (5.0 g, 52.0 mmol) was suspended in 200 mL of methanol. Methylamine (20 mL of 33% solution in methanol) was added. After stirred for 15 minutes, NaBH4(3.95 g, 0.10 mol) was added portion-wise. The reaction mixture was then heated at 50° C. for 2 h under N2. The solvent was removed. The solid was washed with CH2Cl2and filtered. The CH2Cl2solution was dried over MgSO4, concentrated, and dried under vacuum to give the methylamine as a yellow oil. This oil was dissolved in a 1:1 solution of CH2Cl2and THF. To it was added Et3N (7.94 mL, 57.0 mmol) and benzylchloroformate (7.4 mL, 52.0 mmol). The mixture was stirred at room temperature under N2for 1 h. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried over MgSO4, and concentrated. The mixture was refluxed with 15 mL of TFA for 30 minutes to convert most of the bis-acylated byproduct to the desired product. The TFA was removed. It was dissolved in EtOAc and washed with Saturated aqueous NaHCO3and brine. The mixture was dried over MgSO4, concentrated, and chromatographed with 1:1 EtOAc/hexane to give 6.56 g off-white solid (51.4% yield). MS (AP+): 246.3, (M+H)+.1HNMR (CDCl3): δ 7.35 (s, 6H), 6.90 (s, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.00 (s, 3H).

Part F: Preparation of benzyl (1-{4-[1-(4-methoxyphenyl)-7-methylene-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl(methyl)carbamate

Benzyl 1H-imidazol-2-ylmethyl(methyl)carbamat (1.17 g, 4.76 mmol) from Part E, 1-[2-trifluoroacetamidomethyl-phenyl]-3-trifluoromethyl-6-[4-Iodo-2-fluorophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one from Part D (1.63 g, 3.18 mmol), CuI (0.12 9, 20%), K2CO3(0.66 g, 4.76 mmol), 1,10-phenanthroline (56 mg, 20%) were added together with 100 mL of DMSO. The mixture was degassed and then heated at 130° C. under N2for 12 h. The mixture was cooled and aqueous NH4OH (200 mL of of 10% NH4OH) was added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined EtOAc mixture was washed with brine, dried over MgSO4, concentrated, and chromatographed with EtOAc to give 1.34 g of the desired product (66.9%). MS (ES+): 631.3, (M+H)+.

Part H: Preparation of N-[(1-{4-[1-(4-Methoxyphenyl)-7-oxo-3-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl]-N-methylacetamide, trifluoroacetic acid salt

Part A: Preparation of ethyl (2Z)-chloro[(4-methoxyphenyl)hydrazono]ethanoate

Part B: Preparation of ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part C: Preparation of 2-(methylaminomethyl)imidazole

2-Imidazolecarboxaldehyde (50.0 g, 52.5 mmol) and MeOH (700 mL) were added together in a 2 L round-bottomed flask. A solution of methylamine in EtOH (200 mL of 33%) was added. The mixture was stirred at RT under N2for 30 minutes and NaBH4(37 g, 100 mmol) was added portion wise in 35 minutes. The resulting mixture was stirred at RT for 1 h, then heated at 55° C. for 2 h. The solvents were removed in vacuo. The residue was washed with CH2Cl2and filtered. The filtrate was washed with brine, dried over MgSO4. It was concentrated and dried under vacuum to give 42.7 g of the desired product as a yellow oil.1HNMR (CDCl3) δ 6.95 (s, 2H), 3.85 (s, 2H), 2.42 (s, 3H) ppm.

Part D: Preparation of ethyl 1-(4-methoxyphenyl)-6-(4-{2-[(methylamino)methyl]-1H-imidazol-1-yl}phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-]pyridine-3-carboxylate

Part F: Preparation of 6-[4-(2-{[Acetyl(methyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Product from Part E (115 mg, 0.21 mmol) was dissolved in dioxane (20 mL) and treated with NH4OH (20 mL). The flask was stoppered and the mixture stirred at room temperature for 54 hours. The solvents were removed in vacuo and the residue purified away from remaining starting material by flash chromatography using MeOH:CHCl3:NH4OH (20:1000:2 to 10:100:1). It was then was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 113 mg of the final product as the TFA salt. MS (ES+): 514.4, (M+H)+.1HNMR (CD3OD) δ 7.69 (d, 2H), 7.65-7.57 (m, 5H), 7.47 (d, 2H), 6.95 (d, 2H), 4.68 (s, 2H), 4.16 (t, 2H), 3.80 (s, 3H), 3.32 (t, 2H), 2.96 (s, 3H), 2.01 (s, 3H) ppm.

Part A: Preparation of 1-(4-methoxyphenyl)-6-(4-{2-[(methylamino)methyl]-1H-imidazol-1-yl}phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part B: Preparation of 6-[4-(2-{[ethylcarbonyl(methyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part A: Preparation of ethyl 1-(4-methoxyphenyl)-6-{4-[2-({methyl[(methylamino)carbonyl]amino}methyl)-1H-imidazol-1-yl]phenyl}-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part B: Preparation of 1-(4-methoxyphenyl)-6-{4-[2-({methyl[(methylamino)carbonyl]-amino}methyl)-1H-imidazol-1-yl]phenyl}-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part A: Preparation of ethyl 6-[4-(2-{[(methoxycarbonyl)(methyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part B: Preparation of Methyl (1-{4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl(methyl)carbamate, trifluoroacetic acid salt

Part A: Preparation of ethyl 1-(4-methoxyphenyl)-6-[4-(2-{[methyl(methylsulfonyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part B: Preparation of 1-(4-Methoxyphenyl)-6-[4-(2-{[methyl(methylsulfonyl)amino]-methyl}-1H-imidazol-1-yl)phenyl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part A: Preparation of N-[2-(ethylaminomethyl)]-1H-imidazole

2-Imidazolecarboxyaldehyde (2.5 g, 26 mmol) was suspended in 100 mL of methanol. Ethylamine (2.0 M in THF) was added. After stirring for 30 minutes at room temperature, NaBH4(1.98 g, 52 mmol) was added portion-wise. The reaction mixture was then heated at 50° C. for 2 h under N2. The solvent was removed. The solid was washed with CH2Cl2and filtered. The CH2Cl2solution was dried over MgSO4, concentrated, and dried under vacuum to afford 3.4 g of final product as a yellow oil.1HNMR (CDCl3) δ 7.04 (s, 2H), 3.91 (s, 2H), 2.69 (q, 2H), 1.12 (t, 3H) ppm.

Part B: Preparation of 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part D: Preparation of 6-[4-(2-{[Acetyl(ethyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part A: Preparation of N-[2-(n-propylaminomethyl)]-1H-imidazole

Part C: Preparation of 6-[4-(2-{[Acetyl(n-propyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part A: Preparation of N-[2-(i-propylaminomethyl)]-1H-imidazole

Part C: Preparation of 6-[4-(2-{[Acetyl(n-propyl)amino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Imidazole (6.8 g, 100 mmol) and benzoyl chloride were added together in acetonitrile (200 mL). Triethylamine (40.4 g, 400 mmol) was added dropwise and the mixture stirred at room temperature for 18 hours. The precipitate was filtered off and washed with water and then dried under vacuum to afford 12.3 g of white solid. This solid was suspended in MeOH (150 mL). Iso-propanol saturated with HCl (30 mL) was then added and the mixture stirred at reflux for 18 hours. The solvents were removed in vacuo and the solid washed with acetone and dried under vacuum to afford 2.81 g of off-white solid as final product.1HNMR (CD3OD) δ 7.66 (s, 2H), 4.89 (bs, 2H) ppm.

Part B: Preparation of 6-{4-[2-(aminomethyl)-1H-imidazol-1-yl]phenyl}-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part C: Preparation of 6-[4-(2-{[ethylcarbonylamino]methyl}-1H-imidazol-1-yl)phenyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part A: Preparation of (1Z)-1-[chloro(methylsulfonyl)methylene]-2-(4-methoxyphenyl)hydrazine

Part B: Preparation of 6-(4-iodophenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The product of Part A (2.60 g, 10 mol) was stirred with 1-(4-iodophenyl)-3-(4-morpholinyl)-5,6-dihydro-2(1H)-pyridinone (3.80 g, 10 mol) prepared in Part B of Example 1 and triethylamine (2.76 mL, 20 mol) in EtOAc (30 mL). The mixture was heated at 70° C. under N2for 12 h. The reaction mixture was cooled to 5° C., aqueous HCl (12.4 mL of 4N) was added dropwise. The cooling bath was removed and the mixture was stirred at RT for 4 h. A small amount of hexane (5 mL) and water (10 mL) were added. The precipitate formed was filtered, washed with water and hexane, and dried to afford 4.15 g (80%) of the desired product.1HNMR (CDCl3) δ 7.66 (d, 2H), 7.44 (d, 2H), 7.05 (d, 2H), 6.90 (d, 2H), 4.08 (t, 2H), 3.80 (s, 3H), 3.35 (t, 2H), 3.28 (s, 3H) ppm.

The product from Part B (4.15 g, 7.94 mmol), 2-(methylaminomethyl)imidazole from Part C of Example 6. (1.93 g, 16.67 mmol), K2CO3(4.39 g, 31.76 mmol), CuI (1.51 g, 7.94 mmol) were added together with 50 mL of DMSO. The mixture was degassed and then heated at 130° C. under N2for 4 h. The mixture was cooled, EtOAc and 8% aqueous NH4OH were added. The mixture was filtered through Celite® and washed with EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc. The aqueous layer was extracted with CHCl3again. The EtOAc and CHCl3extracts were washed with water and brine and dried over MgSO4separately. They were then combined, concentrated, and chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH to give 2.79 g of the desired product. This material was further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 2.5 g of the bis-TFA salt. MS (ES+): 507.4, (M+H)+.1HNMR (DMSO-d6) δ 7.60-7.02 (m, 10H), 4.28 (s, 2H), 4.16 (t, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 3.25 (t, 2H), 2.65 (s, 3H) ppm.

Part D: Preparation of N-[(1-{4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl]-N-methylacetamide trifluoroacetic acid salt

The product from Part B of Example 22 (0.52 g, 1.00 mmol), 2-(ethylaminomethyl)imidazole from Part A of Example 18. (0.26 g, 2.10 mmol), K2CO3(0.55 g, 4.00 mmol), CuI (0.19 g, 1.00 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130° C. under N2for 4 h. The mixture was cooled, CHCl3and 8% aqueous NH4OH were added. The mixture was filtered through Celite® and washed with CHCl3. The two layers were separated and the aqueous layer was extracted with CHCl3. The organic extract was washed with water and brin, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH, then further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 351 mg of the bis-TFA salt. MS (ES+): 521.3, (M+H)+.1HNMR (DMSO-d6) δ 7.60-7.02 (m, 10H), 4.28 (s, 2H), 4.16 (t, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 3.25 (t, 2H), 3.04 (q, 2H), 1.18 (t, 3H) ppm.

Part B: Preparation of N-ethyl-N-[(1-{4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl]acetamide trifluoroacetic acid salt

Part A: Preparation of 6-(4-{2-[(isopropylamino)methyl]-1H-imidazol-1-yl}phenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The product from Part B of Example 22 (0.52 g, 1.00 mmol), 2-(I-propylaminomethyl)imidazole from Part A of Example 20. (0.29 g, 2.10 mmol), K2CO3(0.55 g, 4.00 mmol), CuI (0.19 g, 1.00 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130° C. under N2for 4 h. The mixture was cooled, CHCl3and 8% aqueous NH4OH were added. The mixture was filtered through Celite® and washed with CHCl3. The two layers were separated and the aqueous layer was extracted with CHCl3. The organic extract was washed with water and brin, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH, then further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 270 mg of the bis-TFA salt. MS (ES+): 535.5, (M+H)+.1HNMR (DMSO-d6) δ 7.60-7.02 (m, 10H), 4.26 (s, 2H), 4.16 (t, 2H), 3.82 (s, 3H), 3.39 (m, 1H), 3.38 (s, 3H), 3.25 (t, 2H), 1.22 (d, 6H) ppm.

Part B: Preparation of N-isopropyl-N-[(1-{4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl]acetamide trifluoroacetic acid salt

The product from Part B of Example 22 (0.52 g, 1.00 mmol), 2-(ethylaminomethyl)imidazole from Part A of Example 19.(0.29 g, 2.10 mmol), K2CO3(0.55 g, 4.00 mmol), CuI (0.19 g, 1.00 mmol) were added together with 6 mL of DMSO. The mixture was degassed and then heated at 130° C. under N2for 4 h. The mixture was cooled, CHCl3and 8% aqueous NH4OH were added. The mixture was filtered through Celite® and washed with CHCl3. The two layers were separated and the aqueous layer was extracted with CHCl3. The organic extract was washed with water and brin, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel with 1:1 EtOAc/hexane and 8:1 CHCl3/MeOH, then further purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 300 mg of the bis-TFA salt. MS (ES+): 535.4, (M+H)+.1HNMR (DMSO-d6) δ 7.60-7.02 (m, 10H), 4.28 (s, 2H), 4.16 (t, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 3.25 (t, 2H), 2.95 (t, 2H), 1.60 (m, 2H), 0.87 (t, 3H) ppm.

Part B: Preparation of N-[(1-{4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}-1H-imidazol-2-yl)methyl]-N-propylacetamide trifluoroacetic acid salt

Product from Part A (150 mg, 0.20 mmol), acetic acid (11.6 μL, 0.20 mmol), triethylamine (110 μL, 0.40 mmol), and HBTU (76.0 mg, 0.20 mmol) were added together with DMF (5 mL). The mixture was stirred at RT under N2for 12 h. Water was added, followed by aqueous NaOH to adjust the pH to 8-9.

Part A: Preparation of ethyl 6-(2′-formyl-1,1′-biphenyl-4-yl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part B: Preparation of ethyl 1-(4-methoxyphenyl)-6-{2′-[(methylamino)methyl]-1,1′-biphenyl-4-yl}-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part C: Preparation of ethyl 1-(4-methoxyphenyl)-6-[2′-({methyl[(methylamino)carbonyl]amino}methyl)-1,1′-biphenyl-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part D: Preparation of 1-(4-methoxyphenyl)-6-[2′-({methyl[(methylamino)carbonyl]amino}methyl)-1,1′-biphenyl-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

2-Imidazolecarboxyaldehyde (5.0 g, 52.0 mmol) was suspended in 200 mL of methanol. Methylamine (20 mL of 33% solution in methanol) was added. After stirred for 15 minutes, NaBH4(3.95 g, 0.10 mol) was added portion-wise. The reaction mixture was then heated at 50° C. for 2 h under N2. The solvent was removed. The solid was washed with CH2Cl2and filtered. The CH2Cl2solution was dried over MgSO4, concentrated, and dried under vacuum to give the methylamine as a yellow oil. This oil was dissolved in a 1:1 solution of CH2Cl2and THF. To it was added Et3N (7.94 mL, 57.0 mmol) and benzylchloroformate (7.4 mL, 52.0 mmol). The mixture was stirred at room temperature under N2for 1 h. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried over MgSO4, and concentrated. The mixture was refluxed with 15 mL of TFA for 30 minutes to convert most of the bis-acylated byproduct to the desired product. The TFA was removed. It was dissolved in EtOAc and washed with Saturated aqueous NaHCO3and brine. The mixture was dried over MgSO4, concentrated, and chromatographed with 1:1 EtOAc/hexane to give 6.56 g off-white solid (51.4% yield). MS (AP+): 246.3, (M+H)+.1HNMR (CDCl3): δ 7.35 (s, 6H), 6.90 (s, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.00 (s, 3H).

Part B: Preparation of benzyl {1-[4-({[1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)-3-fluorophenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate

Benzyl 1H-imidazol-2-ylmethyl(methyl)carbamate from Part A (3.60 g, 14.69 mmol), 2-fluoro-4-iodoaniline (3.50 g, 14.69 mmol), K2CO3(2.23 g, 16.16 mmol), 1,10-phenanthroline (0.13 g, 0.73 mmol), CuI (0.14 g, 0.73 mmol), and DMSO (60 mL) were added together and degassed. The mixture was then heated at 130° C. under N2for 12 h. The mixture was cooled, 14% aqueous NH4OH (200 mL) and EtOAc (200 mL) were added. The mixture was filtered through Celite® and washed with EtOAc. The filtrate was extracted with EtOAc, the combined organic solution was washed with brine, and dried over MgSO4. It was concentrated and purified by chromatography on silica gel with 50-100% hexane in EtOAc to give 3.46 g of the desired product (67%). MS (ES+): 355.2, (M+H)+.

Part C: Preparation of benzyl {1-[4-({[1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)-3-fluorophenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate

1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid prepared as described in WO 98/57951 (1.00 g, 3.34 mmol) was stirred in 20 mL of CH2Cl2at room temperature under N2. Oxalyl chloride (0.43 mL, 5.01 mmol) was added, followed by a few drops of DMF. The mixture was stirred for 2 h. The solvent was removed and the resulting solid was dried under vacuum. This solid was then dissolved in 50 mL of CH2Cl2, benzyl {1-[4-({[1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)-3-fluorophenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate from Part B (1.32 g, 3.34 mmol) was added, followed by DMAP (1.02 g, 8.35 mmol). The mixture was stirred at room temperature under N2for 12 h. It was diluted with CH2Cl2washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by chromatography on silica gel with 50-100% hexane in EtOAc to give 1.10 g of the desired product (52%). MS (ES+): 636.1, (M+H)+.

Part D: Preparation of N-[4-(2-{[(methyl)amino]methyl}-1H-imidazol-1-yl)-2-fluorophenyl]-1-(3-amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

Acetohydroxamic acid (0.40 g, 5.34 mmol) was dissolved in 10 mL of DMF. K2CO3(0.98 g, 7.12 mmol) was added, followed by 1 mL of water. The mixture was stirred at room temperature under N2for 30 minutes and a solution of benzyl {1-[4-({[1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)-3-fluorophenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate from Part C (1.13 g, 1.78 mmol) in 10 mL of DMF was added. The resulting mixture was stirred at room temperature under N2for 12 h. Water was added to the reaction mixture. The precipitate formed was filtered and dried. MS (ES+): 647.1, (M−H)−.

The above solid was refluxed with 20 mL of TFA under N2for 30 minute. The TFA was removed. The residue was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 0.61 g of the desired product as the TFA salt. MS (ES+): 515.0, (M+H)+.

Part E: Preparation of N-[4-(2-{[acetyl(methyl)amino]methyl}-1H-imidazol-1-yl)-2-fluorophenyl]-1-(3-amino-1,2-benzisoxazol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

This compound was prepared using the same methods as described in Part A of Example 22. MS (ES−): 274.1, 276.1, (M−H)−.

Part B: Preparation of ethyl 1-(3-cyano-4-fluorophenyl)-3-(methylsulfonyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

The product from Part A (3.8 g, 13.8 mmol) was suspended in toluene (50 mL) and cooled in an ice bath. Triethylamine (3.14 g, 31.1 mmol) was added, followed by ethyl acrylate (4.14 g, 41.4 mmol) dropwise. The mixture was stirred at room temperature under N2for 24 h. The mixture was refluxed for 4 h. The mixture was diluted with EtOAc and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated. The crude product was purified by flash chromatography using EtOAc:Hexane (2:3 to 1:1) to afford 3.79 g of the desired product. MS (ES−): 374.2, (M+Cl)−.

Part C: Preparation of ethyl 1-(3-cyano-4-fluorophenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxylate

The product from Part B (3.79 g, 11.2 mmol) was dissolved in THF (50 mL) and cooled in an ice bath. N-Chlorosuccinimide (1.64 g, 12.3 mmol) was added and the mixture was stirred at room temperature under N2for 1 h. The mixture was diluted with Et2O and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated in vacuo to afford 3.92 g of the desired product. MS (ES+): 360.2, (M+Na)+.

Part D: Preparation of 1-(3-cyano-4-fluorophenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxylic acid

The product from Part C (3.79 g, 11.2 mmol) was dissolved in THF (30 mL) and then diluted with MeOH (10 mL) and H2O (10 mL). Lithium hyroxide monohyrate (706 mg, 16.8 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with 1.0 N hyrochloric acid (17 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated in vacuo to afford 3.35 g of the desired product. MS (ES−): 308.2, (M−H)−.

Part E: Preparation of benzyl {1-[4-({[1-(3-cyano-4-fluorophenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate

The product from Part D and the product from Part A of Example 33 were coupled using the same methods described in Part C of Example 33 (78% yield). MS (ES+): 526.5 (M+H)+.

Part F: Preparation of 1-(3-amino-1,2-benzisoxazol-5-yl)-N-(4-{2-[(methylamino)methyl]-1H-imidazol-1-yl}phenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxamide

This compound was prepared using the same methods as described in Part D of Example 33 using the product from Part E as the starting material (yield 12%). MS (ES+): 659.5 (M+H)+, MS (ES+): 525.4 (M+H)+.

Part A: Preparation of ethyl 1-(4-methoxyphenyl)-3-(methylsulfonyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

The product from Part A of example 22 (5 g, 19.1 mmol) was suspended in toluene (50 mL) and cooled in an ice bath. Triethylamine (2.9 g, 28.7 mmol) was added, followed by ethyl acrylate (4.14 mL, 38.2 mmol) dropwise. The mixture was stirred at room temperature under N2for 24 h. The mixture was diluted with EtOAc and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated. The crude product was purified by flash chromatography using EtOAc:Hexane (1:2 to 2:3) to afford 5.21 g of the desired product. MS (ES−): 325.3, (M−H)−.

Part B: Preparation of ethyl 1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxylate

The product from Part A (5.2 g, 16 mmol) was dissolved in THF (50 mL) and cooled in a 0 C ice bath. N-Chlorosuccinimide (2.34 g, 17.5 mmol) was added and the mixture was stirred at room temperature under N2for 1 h. The mixture was diluted with Et2O and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated in vacuo to afford 5.32 g of the desired product. MS (ES+): 325.3, (M+H)+.

Part C: Preparation of 1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxylic acid

The product from Part B (5.3 g, 16.0 mmol) was dissolved in THF (30 mL) and then diluted with MeOH (10 mL) and H2O (10 mL). Lithium hyroxide monohyrate (1.03 g, 24.5 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was quenched with 1.000 N hyrochloric acid (25 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated in vacuo to afford 4.76 g of the desired product. MS (ES−): 295.2, (M−H)−.

Part D: Preparation of benzyl {1-[4-({[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]-1H-imidazol-2-yl}methyl(methyl)carbamate

The product from Part C (696 mg, 2.35 mmol) was suspended in CH2Cl2(10 mL). Oxalyl chloride (0.41 mL, 4.7 mmol) was added followed by a drop of DMF and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2(10 mL) and treated with 4-dimethylaminopyridine (1.73 g, 14.1 mmol) and Part B of Example 33 (1.05 g, 4.23 mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with CH2Cl2and washed with H2O and brine. The organic solution was then dried over MgSO4and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc:EtOH:Hexane (10:2:10 to 10:3:10) to elute 949 mg of the desired product. MS (ES+): 633.5, (M+H)+.

Part E: Preparation of 1-(4-methoxyphenyl)-N-(4-{2-[(methylamino)methyl]-1H-imidazol-1-yl}phenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxamide

The product from Part D (940 mg, 1.49 mmol) was dissolved in EtOH (30 mL) and trifluoroacetic acid (0.5 mL) added. 20% Palladium Hydroxide was then added under N2and the mixture shaken under 55 psi H2for 18 h. The mixture was filtered through Celite® under a N2purge and was concentrated in vacuo. The residue was purified by reverse phase HPLC (C18 reverse phase column, eluted with a H2O/CH3CN gradient with 0.05% TFA) to give 76 mg of the desired product as the TFA salt. MS (ES+): 499.4, (M+H)+.

Part F: Preparation of N-[4-(2-{[methylsulfonylamino]methyl}-1H-imidazol-1-yl)-2-fluorophenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxamide, trifluoroacetic acid salt

Part A: Preparation of methyl 4-(2-furyl)-2,4-dioxobutanoate

Sodium Methoxide (25% in methanol, 11.9 g, 55 mmol) was treated dropwise (over 30 minutes) with a solution of 2-acetylfuran (5.01 mL, 50 mmol) and dimethyloxalate (5.14 mL, 50 mmol) in THF. The resulting suspension was stirred at room temperature for 18 h. The solid was filtered, washed with ether, dissolved in EtOAc/H2O, and acidified to pH 2-3 with 10% HCl. The mixture was then extracted with more EtOAc. The organic layers was combined, dried over MgSO4, filtered, concentrated, and dried under vacuum to afford desired product (10.2 g, 95%).

Part B: Preparation of methyl 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate

The product from Part A (1.96 g, 10 mmol), p-anisidine (1.23 g 10 mmol), and p-Toluenesulfonic acid (1.90 g, 10 mmol) were dissolved in methanol and the resulting solution refluxed for 3 h. The solvents were removed in vacuo and the residue filtered through a silica gel bed with ethyl acetate. The solvents were removed in vacuo and the residue crystallized from ether/hexane to afford desired product (>85% yield).

Part C: Preparation of 3-(methoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid

The compound from Part B (1.0 g, 3.4 mmol) was dissolved in acetonitrile (10 mL) and cooled in a 0 C ice bath. NaH2PO4(2.32 g, 16.8 mmol) in H2O (4 mL) was then added followed by NaClO2in H2O (12 mL) and the mixture stirred at room temperature for 2 h. The mixture was quenched with sat. sodium bisulfite and extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over MgSO4and concentrated in vacuo. The residue was triturated with Et2O and the solid collected and dried under vacuum to afford 190 mg of desired product.1HNMR (DMSO-d6) δ 7.40 (m, 3H), 7.05 (d, 2H), 3.83 (s, 3H), 3.82 (s, 3H).

Part D: Preparation of methyl 5-({[4-(2-{[[(benzyloxy)carbonyl](methyl)amino]methyl}-1H-imidazol-1-yl)phenyl]amino}carbonyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate

The product from Part C and the product from Part B of Example 33 were coupled using the same methods as described in Part D of Example 35. MS (ES+): 613.5 (M+H)+.

Part E: Preparation of methyl 1-(4-methoxyphenyl)-5-{[(4-(2-[(methylamino)methyl]-1H-imidazol-1-yl}phenyl)amino]carbonyl)-1H-pyrazole-3-carboxylate

The product from Part D was hydrogenated using the same methods as described in Part E of Example 35. MS (ES+): 479.5 (M+H)+.

Part F: Preparation of methyl 1-(4-methoxyphenyl)-5-({[4-(2-{[methyl(methylsulfonyl)amino]methyl}-1H-imidazol-1-yl)phenyl]amino}carbonyl)-1H-pyrazole-3-carboxylate

Product from Part E (100 mg, 0.17 mmol) was dissolved in CH2Cl2(10 mL). Triethylamine (170 mg, 1.7 mmol) was added, followed by methanesulfonyl chloride (39 mg, 0.34 mmol). The mixture was stirred at room temperature under N2for 18 h. The mixture was diluted with CH2Cl2and washed with H2O and brine and the solvent was removed in vacuo. The crude product was purified by flash chromatography using MeOH:CHCl3(2%) to elute 58 mg of the final product. MS (ES+): 557.4 (M+H)+.

Part G: Preparation of N-[4-(2-{[methylsulfonylamino]methyl}-1H-imidazol-1-yl)-2-fluorophenyl]-1-(4-methoxyphenyl)-3-(aminocarbonyl)-1H-pyrazole-5-carboxamide, trifluoroacetic acid salt (DPC-AN3174-17)

Part A. Preparation of lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate

A 1-L flame-dried flask was charged with 130 mL of LiHMDS (130 mmol; 1.0 M in THF) and 410 mL of ethyl ether. The resulting solution was cooled to −78° C. and 2-acetylfuran (14 g, 12 m mmol) was added in one portion. After 5 min, di-tert-butyl oxalate was added dropwise over 1 h as a solution in 100 mL of ether. The resulting mixture was warmed to 23° C. over a period of 3 h and was maintained at room temperature for 20 h. The mixture was then filtered, and the resulting beige precipitate was washed with 100 mL of ether. The filter cake was dried in a vacuum oven for 1 h to afford lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (25 g, 83%) as a cream colored solid.1HNMR (DMSO-d6) δ 7.75 (t, 1H), 6.96 (m, 1H), 6.56 (m, 1H), 3.34 (s, 2H), 1.46 (s, 9H).

Part C. Preparation of 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate

To the product from Part B (10 g, 28 mmol) was added 125 mL of dichloromethane and 125 mL of trifluoroacetic acid. The resulting black solution was maintained at room temperature under nitrogen for 2 h and was then concentrated to dryness. The resulting solid was dried in a vacuum oven for 4 h to afford 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate (8.4 g, 99%) as a brown solid. LC/MS (ES+): 298.1 (M+H)+.1HNMR (CD3OD) δ 7.90 (m, 1H) 7.75 (m, 1H), 7.51 (s, 1H), 7.46 (t, 1H), 6.98 (s, 1H), 6.47 (m, 1H), 6.35 (m, 1H).

Part D. Preparation of 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxamide

To the product (4.1 g, 14 mmol) from Part C was added 23 mL of dichloromethane and 2.0 M oxalyl chloride (10 mL, 21 mmol) in dichloromethane. After dropwise addition of N,N-dimethylformamide (10 drops) to the brown mixture, the mixture became clear over a period of 30 min. When no more gas evolved, the brown solution was concentrated. The resulting residue was redissolved in 100 mL of dichloromethane and 0.5 M ammonia in dioxane (110 mL, 55 mmol) was added via cannula. After 30 min, the resulting suspension was concentrated and poured into water. The aqueous layer was washed with ethyl acetate (3×70 mL), and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The resulting residue was dissolved in 10 mL of dichloromethane and 50 mL of hexanes were added. The resulting suspension was filtered, and the filter cake was washed with 50 mL of hexanes. The filter cake was dried in a vacuum oven to afford 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxamide (2.5 g, 62%) as a brown solid. LC/MS (ESI+): 297.1 (M+H)+.1HNMR (CDCl3) δ 7.75 (m, 1H), 7.64 (m, 1H), 7.42 (s, 1H), 7.33 (t, 1H), 7.16 (s, 1H), 6.79 (br s, 1H), 6.46 (m, 1H), 6.36 (m, 1H), 5.50 (br s, 1H).

Part E. Preparation of 3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid

To the product (2.5 g, 8.3 mmol) from Part D was added water (51 mL), 5% aqueous sodium dihydrogenphosphate (35 mL), and tert-butanol (51 mL). The resulting mixture was warmed to 60° C., and potassium permanganate (8.0 g, 51 mmol) was added over a period of 10 min. After an additional 10 min, the resulting purple slurry was cooled to 0° C., and the reaction was quenched by the addition of 200 mL of saturated aqueous sodium bisulfite. The resulting mixture was filtered, washed with 300 mL of water, and the filtrate was acidified with concentrated hydrogen chloride. The aqueous layer was extracted with ethyl acetate (6×100 mL) and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. Concentration afforded 3-(aminocarbonyl)-1(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid (1.6 g, 71%) as a yellow solid. LC/MS (ESI+): 275.1 (M+H)+.1HNMR (CD3OD) δ 8.03 (m, 1H), 7.90 (m, 1H), 7.5 (t, 1H), 7.44 (s, 1H).

Part F. Preparation of N-(1H-imidazol-2-ylmethyl)-N-methylamine

To a flame-dried 500-mL flask was added methanol (200 mL), 2-imidazolecarboxaldehyde (5.0 g, 52 mmol), and 8.0 M methylamine (20 mL, 160 mmol). The reaction was stirred for 45 min, at which time, all carboxaldehyde dissolved. Sodium borohydride (4.0 g, 104 mmol) was added in four equal portions over a period of 2 min, resulting in a vigorous exotherm and a reaction temperature of 45° C. The reaction temperature was increased to 50° C. and maintained at this temperature for 2 h. The reaction was then cooled, concentrated, and dichloromethane (200 mL) was added. The mixture was concentrated, and dichloromethane (200 mL) was again added. The resulting mixture was filtered, the filter cake was washed with dichloromethane (2□50 mL), and the filtrate was concentrated. The resulting viscous yellow oil solidified upon standing to afford N-(1H-imidazol-2-ylmethyl)-N-methylamine as a yellow solid (5.5 g, 95%) which was used without further purification.1HNMR (CDCl3) δ 6.99 (s, 2H), 3.87 (s, 2H), 2.46 (s, 3H)

Sodium cyanoborohydride (1.54 g, 25 mmol) was added in one portion to a stirring orange solution of 5-iodo-1H-indole (6.0 g, 25 mmol) in glacial acetic acid (350 mL). After 24 h, the orange solution was concentrated. To the resulting red residue was added tetrahydrofuran (250 mL) and di-tert-butyl dicarbonate (16 g, 74 mmol) followed by saturated aqueous sodium bicarbonate (20 mL). The resulting mixture was stirred for 24 h and was then poured into-aqueous 1N hydrogen chloride (70 mL). The layers were separated, and the aqueous layer was washed with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate and concentrated. The resulting residue was dissolved in THF (100 mL), and benzyl amine (6 mL, 55 mol) was added. The resulting solution was stirred for 1.5 h and was then poured into 1N hydrogen chloride (70 mL). The layers were separated and the aqueous layer was washed with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated. Purification of the resulting residue by flash column chromatography (5% ethyl acetate in hexanes) affored tert-butyl 5-iodo-1-indolinecarboxylate (3.9 g, 45%) as a white solid. LC/MS (ESI+): 346.1 (M+H)+.

A flame-dried flask was charged with methyl sulfoxide (46 mL), anhydrous potassium carbonate (1.28 g, 9.3 mmol), and N-(1H-imidazol-2-ylmethyl)-N-methylamine (520 mg, 4.6 mmol). The product (0.80 g, 2.3 mmol) from Part G was added, and the mixture was degassed by alternating treatment with vacuum and nitrogen (×3). Copper(I) iodide (440 mg, 2.3 mmol) was added, and the reaction mixture was again degassed. The green mixture was maintained at 130° C. for 2.5 h and was then cooled to room temperature. The mixture was poured into saturated aqueous ammonium hydroxide (100 mL) and the aqueous layer was washed with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous ammonium hydroxide (50 mL), water (2×50 mL), and saturated aqueous sodium chloride (50 mL). The organic layer was then dried over sodium sulfate, concentrated, and the resulting green-black residue was purified by radial chromatography (5% methanol in dichloromethane) to afford tert-butyl 5-{2-[(methylamino)methyl]-1H-imidazol-1-yl}-1-indolinecarboxylate (0.40 g, 52%) as a brown oil. LC/MS (ESI+): 329.3 (M+H)+.

To the product from Part H (0.20 g, 0.61 mmol) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Acetyl chloride (0.048 mL, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous 1N hydrogen chloride (10 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, and concentrated to give tert-butyl 5-(2-{[acetyl(methyl)-amino]methyl}-1H-imidazol-1-yl)indolinecarboxylate (230 mg, 100%) as a brown oil). LC/MS (ESI+): 371.3 (M+H)+.

Part J. Preparation of N-{[1-(2,3-dihydro-1H-indol-5-yl)-1H-imidazol-2-yl}methyl}-N-methylacetamide

To the product from Part I (0.23 mg, 0.62 mmol) was added 50% triflouoroacetic acid in dichloromethane (6 mL). The resulting brown solution was stirred for 2 h and was then concentrated. The resulting residue was poured into saturated aqueous sodium bicarbonate (30 mL), and the aqueous layer was washed with ethyl acetate (4□50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated to give N-{[1-(2,3-dihydro-1H-indol-5-yl)-1H-imidazol-2-yl}methyl}-N-methylacetamide (96 mg, 57%) as a brown oil. LC/MS (ESI+): 271.3 (M+H)+.

To tert-butyl 5-{2-[(methylamino)methyl]-1H-imidazol-1-yl}-1-indolinecarboxylate (0.20 g, 0.61 mmol; from Part H of Example 37) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Methanesulfonyl chloride (0.052, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous 1N hydrogen chloride (10 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, and concentrated to give tert-butyl 5-(2-{[methyl(methylsulfonyl)amino]methyl}-1H-imidazol-1-yl)-1-indolinecarboxylate (250 mg, 100%) as a brown oil). LC/MS (ESI+): 407.3 (M+H)+.

To the product from Part A (0.25 mg, 0.61 mmol) was added 50% triflouoroacetic acid in dichloromethane (6 mL). The resulting brown solution was stirred for 2 h and was then concentrated. The resulting residue was poured into saturated aqueous sodium bicarbonate (30 mL), and the aqueous layer was washed with ethyl acetate (4×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated to give N-[{1-(2,3-dihydro-1H-indol-5-yl)-1H-imidazol-2-yl]methyl}-N-methyl methanesulfonamide (150 mg, 78%) as a brown oil. LC/MS (ESI+): 307.3 (M+H)+.

Part A. Preparation of [1-(2-Formylphenyl)-piperidin-4-yl]carbamic acid t-butyl ester

Part B. Preparation of [1-(2-Methylaminomethylphenyl)piperidin-4-yl]-carbamic acid t-butyl ester

A mixture of the product from Part A (0.5 g, 1.64 mmol) and methylamine hydrochloride (0.22 g, 3.28 mmol) in 1,2-dichloroethane (10 mL) was stirred 5-10 min followed by addition of sodium triacetoxyborohydride (0.52 g, 2.46 mmol). The resulting mixture was stirred for 72 h under N2. The reaction was quenched by addition of 2N NaOH and extracted into Et2O. Purification of the resulting residue by rotary prep TLC (silica gel, CH2Cl2-MeOH-NH4OH 95:5:0.5-90:10:1) to remove some alcohol by-product provided the desired N-methylamine product (0.31 g, 58%). MS (ESI+) m/z 320.4 (M+H)+.

Part C. Preparation of (1-{2-[(Acetylmethylamino)methyl]phenyl}piperidin-4-yl)carbamic acid t-butyl ester

A solution of the product from Part B (0.1 g, 0.313 mmol) in CH2Cl2(1 mL) was cooled in an ice bath under N2with stirring while acetyl chloride (25-30 μl) was added. The whole was stirred overnight at room temperature. The mixture was diluted with additional CH2Cl2and washed with 5% citric acid solution, saturated NaHCO3and brine, then dried over anhydrous Na2SO4, filtered, and evaporated. Purification on 5 g silica gel cartridge eluted with hexane-ethyl acetate (1:1) provided the acetamide as a white foam. This was used without purification in Part D below.

The product from Part C was dissolved in a mixture of CH2Cl2(4 mL) and TFA (1 mL) and stirred overnight at room temperature. Mixture was evaporated in vacuo and the residue triturated with Et2O to provide the amine salt as a sticky solid (32 mg, 39% over two steps). MS (ESI+) m/z 262.3 (M+H)+.

Part E. Preparation of 2-(3-Cyano-4-fluorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (1-{2-[(acetylmethylamino)-methyl]phenyl}piperidin-4-yl)amide

A mixture of 2-(3-cyano-4-fluorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (25 mg, 0.084 mmol), the product from Part D (32 mg, 0.065 mmol), Castro's reagent (43 mg, 0.098 mmol) and N-methylmorpholine (50 μmL, 0.455 mmol) in DMF (1 mL) was stirred overnight at room temperature under N2. The resulting mixture was poured into water and extracted3× into ethyl acetate. The combined extracts were washed with water, saturated NaHCO3, and brine, then dried over anh. Na2SO4, filtered and evaporated to provide the product (41 mg, 90% crude yield) that was used without purification in Part F below.

Part F. Preparation of 2-(3-Aminobenzo[d]isoxazol-5-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (1-{2-[(acetyl-methyl-amino)methyl]phenyl}piperidin-4-yl)amide

Part A. Preparation of 2-[2-(4-Aminopiperidin-1-yl)benzyl]methyl-aminoethanol

The compound from Part A of Example 39 (0.20 g, 0.66 mmol) was charged to a 25 mL reaction vessel, and sodium triacetoxyborohydride (0.21 g, 1.0 mmol), and 5 mL of 1,2-dichloroethane were added. While stirring under N22-aminoethanol (0.04 g, 0.77 mmol) was added. The reaction mixture was stirred for an additional 14 h at room temperature. The mixture was concentrated in vacuo. The crude product was redissolved in 5 mL dioxane and treated with 5 mL of 4N solution of HCl in dioxane. The reaction was stirred under N2for 2 h and then filtered. The resulting white solid was dried under high vacuum for 14 h to provide the desired product (0.210 g, 95% yield).1HNMR (DMSO-d6) δ 8.59-8.42 (bs, 2H), 7.59-7.56 (d, 1H), 7.50-7.47 (t, 1H), 7.35-7.32 (d, 1H), 7.29-7.21 (t, 1H), 4.66-4.34 (m, 4H), 3.77 (bs, 1H), 3.24-3.15 (m, 2H), 2.44 (m, 4H), 2.00 (m, 4H); MS (ESI+) m/z 264.3 (M+H)+.

Part B. Preparation of 2-(4-Methoxyphenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [1-(2-{[(2-hydroxyethyl)methylamino]-methyl}phenyl)piperidin-4-yl]amide

EXAMPLES 42 AND 43

N-(2-{4-[3-cyano-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]-1-piperidinyl}benzyl)-N-methylacetamide, trifluoroacetic acid salt and 6-[1-(2-{[acetyl(methyl)amino]methyl}phenyl)-4-piperidinyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1N-pyrazolo[3,4-c]pyridine-3-carboxamide, trifluoroacetic acid salt

Part B. Preparation of 1′-benzyl-3,3-dichloro-1,4′-bipiperidin-2-one

Part C. Preparation of 1-(1-benzyl-4-piperidinyl)-3-(4-morpholinyl)-5,6-dihydro-2(1H)-pyridinone

The product from Part B (10.56 g, 31.06 mmol) was refluxed in morpholine (50 mL) overnight under N2. LC-MS showed completion of the reaction. Solvent was evaporated. The residue was diluted with EtOAc, washed with H2O (2×), brine (2×), dried over MgSO4, and concentrated to yield light tan foam of 1-(1-benzyl-4-piperidinyl)-3-(4-morpholinyl)-5,6-dihydro-2(1H)-pyridinone (9.85 g, 86%). LC/MS (ESI+), 356.2 (M+H).

Part D. Preparation of ethyl 6-(1-benzyl-4-piperidinyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part E. Preparation of ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-piperidinyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Part F. Preparation of 1-(4-methoxyphenyl)-7-oxo-6-(4-piperidinyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part G. Preparation of 6-[1-(2-formylphenyl)-4-piperidinyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Part H. Preparation of 1-(4-methoxyphenyl)-6-(1-{2-[(methylamino)methyl]phenyl}-4-piperidinyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

A solution of the product from Part H (17 mg, 0.02 mmol), acetyl chloride (0.05 mL), and pyridine (0.05 mL) in anhydrous CH2Cl2(1 mL) was stirred at room temperature for 2 h under N2. Two products (1:5) were detected by LC/MS (ESI+): 531.6 (M+H) and 513.6 (M+H) for the amide (I-1) and the nitrile (I-2), respectively. The mixture was then concentrated in vacuo, and the residue was purified by prep LC-MS (5-98% CH3CN/H2O in a 10-min run) to obtain the product I-1, 6-[1-(2-{[acetyl(methyl)amino]methyl}phenyl)-4-piperidinyl]-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1.6 mg, 10%). LC/MS (ESI+), 531.6 (M+H). And product I-2, N-(2-{4-[3-cyano-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]-1-piperidinyl}benzyl)-N-methylacetamide (8 mg, 50%). LC/MS (ESI+), 513.6 (M+H).

Part A: Preparation of 1-[4-methoxyphenyl]-3-trifluoromethyl-6-[4-iodophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

Part B: Preparation of 6-(4-{2-[(dimethylamino)methyl]-1H-imidazol-1-yl}phenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Part C: Preparation of 6-(4-{2-[(dimethylnitroryl)methyl]-1H-imidazol-1-yl}phenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

The product from part B (100 mg) was dissolved in dichloromethane (20 mL). To this solution was added 3 equivalents of MCPBA and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate and the organic layer separated and concentrated. The title compound was obtained as colorless crystals by purification va reverse phase HPLC and lyophylization. ESI mass spectrum 527 (M+H); HNMR (CDCl3) δ 7.54 (m, 6H), 7.38 (d, 2H), 6.95 (d, 2H), 5.40 (s), 4.20 (t, 2H), 3.82 (s, 3H), 3.50 (s, 6H), 3.20 (t, 2H) ppm.

Part A: Preparation of 1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-6-[4-iodophenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

To 1-(4-iodophenyl)-3-(4-morpholinyl)-4-(trifluoroacetyl)-5,6-dihydro-2(1H)-pyridinone (2.2 g, 4.6 mmol) was added 2-fluoro-5-hydrazinobenzonitrile hydrochloride (1.11 g, 6 mmol) and 50% con. HCl (10 mL), acetic acid (25 mL) and MeOH (30 mL). The reaction was heated to reflux for 24 h, then cooled and concentrated. The residue was extracted with ethyl acetate, washed with water, brine, and sat'd NaHCO3, and dried (Na2SO4). Purification by chromatography on silica gel using 3:1 Hexanes/ethyl acetate as eluent afforded 0.68 g (28%) of a yellow foam. Mass Spec (M−H)−524.9.

Part B: Preparation of 1-[3-cyano-4-fluorophenyl]-3-trifluoromethyl-6-[2′-formyl-1,1′-biphenyl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one

To the iodo compound from Part A (0.67 g, 1.27 mmol) was added 2-formylbenzeneboronic acid (0.29 g, 1.9 mmol), K3PO4(0.95 g, 4.5 mmol) and dioxane (25 mL) and the mixture was degassed with N2for 15 min. Tetrakistriphenylphosphine Palladium (73 mg) was added and the reaction was heated to reflux 1.5 h. The reaction was stripped and purification by chromatography on silica gel using 2:1 Hexanes/ethyl acetate as eluent afforded 0.37 g (58%) of a brown foam. MS (M+H2O)−522.1.

Part C. Preparation of 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2′-bromomethyl)-1,1′-biphenyl-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pryazolo[3,4-c]pyridin-7-one

To the aldehyde from Part B (2 g, 0.3.8 mmol) in 2:1 THF/MeOH (50 mL) at 0° C. was added NaBH4(0.17 g, 0.46 mmol) and the reaction was stirred 30 min. The reaction was concentrated and partitioned between CH2Cl2/H2O. The organic layer was washed with brine and dried (MgSO4) to afford crude alcohol. To acetohydroxamic acid (0.89 g, 11.9 mmol) in DMF (5 mL) was added K2CO3(2.139 g, 15.9 mmol) and several drops of water. After 30 min the above alcohol in DMF (15 mL) was added and the reaction was stirred 24 h. The reaction was concentrated, diluted with water and extracted with ethyl acetate, washed with water and brine and dried (MgSO4) to afford the crude aminobenzisoxazole.

Part D. Preparation of 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2′-{[bis(2-hydroxyethyl)amino]methyl}-1,1′-biphenyl-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pryazolo[3,4-c]pyridin-7-one trifluoroacetic acid salt

Part A. Preparation of benzyl 3-(methylamino)propylcarbamate

To benzyl chloroformate (1 g, 5.8 mmol) in CH2Cl2(25 mL) at 0° C. was added dropwise imidazole (0.79 g, 11.7 mmol) in CH2Cl2(20 mL). After the addition was complete the reaction was stirred at room temperature for 15 min., then washed with 10% citric acid, brine, and dried (MgSO4). The product obtained was combined with N-methyl-1,3-propane diamine (0.6 mL, 5.8 mmol) and DMAP (15 mg) in CH2Cl2(30 mL) and stirred for 24 h. The reaction was stripped, diluted with ethyl acetate, washed with 5% citric acid and brine and dried (MgSO4). Mass Spec (M+H)+223.3

Part B. Preparation of 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2′-{[(3-aminopropyl)(methyl)amino]methyl}-1,1′-biphenyl-4-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pryazolo[3,4-c]pyridin-7-one trifluoroacetic acid salt

Part A. Preparation of 6-(2′-formyl-1,1′-biphenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

6-(4-Iodophenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one from Part B of Example 22 (0.41 g, 0.7 mmol) and 2-formyl phenylboronic acid (0.18 g, 1.1 mmol) was added 2M Na2CO3(1 mL), ethanol(20 mL) and toluene (30 mL) and the mixture was degassed with N2for 15 min. Tetrakistriphenylphosphine Palladium(0) (50 mg) was added and the reaction was heated to reflux 24 h. The reaction was cooled, concentrated and the residue extracted with ethyl acetate, washed with water and dried (MgSO4). Purification by silica gel chromatography using 1:1 hexane/ethyl acetate as eluent afforded 0.28 g (71.8%) of an grey solid; Mass Spec (M+Na)+524.

Part B. Preparation of 6-(2′-{[(2-hydroxyethyl)(methyl)amino]methyl}-1,1′-biphenyl-4-yl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-1H-pryazolo[3,4-c]pyridin-7-one trifluoroacetic acid salt

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