# Patent

## Title
Pyrazolobenzamides and derivatives as factor Xa inhibitors

## Abstract

The present application describes pyrazolobenzamides and derivatives thereof of Formula I:

P4-P-M-M4I

or pharmaceutically acceptable salt forms thereof. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims the priority benefit of U.S. Provisional Application No. 60/622,236, filed Oct. 26, 2004, which is expressly incorporated fully herein by reference


FIELD OF THE INVENTION
This invention relates generally to pyrazolobenzamides and derivatives thereof 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 of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, 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, but are not limited to: (a) pharmaceutical properties; (b) dosage requirements; (c) factors which decrease blood concentration peak-to-trough characteristics; (d) factors that increase the concentration of active drug at the receptor; (e) factors that decrease the liability for clinical drug-drug interactions; (f) factors that decrease the potential for adverse side-effects; and (g) factors that improve manufacturing costs or feasibility.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel pyrazolobenzamides and derivatives thereof that are useful as factor Xa inhibitors or pharmaceutically acceptable salts, solvates, or prodrugs thereof.
The present invention also provides processes and intermediates for making the compounds of the present invention or a stereoisomer or a pharmaceutically acceptable salt, solvate, or prodrug form 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, solvate, or prodrug form thereof.
The present invention provides a method for treating thromboembolic disorders comprising administering to a mammal 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, solvate, 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, solvate, or prodrug 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, solvate, or prodrug form thereof in an amount effective to treat a thromboembolic disorder.
The present invention provides novel lactam-containing compounds and derivatives thereof for use in therapy.
The present invention provides the use of novel lactam-containing 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 pyrazolobenzamide compounds of Formula I:

P4-P-M-M4  I

wherein P, P4, M, and M4 are defined below, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.


DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In a first embodiment, the present invention provides a novel compound of Formula I:

P4-P-M-M4  I

or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form 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 R1a and 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 R1a and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
        alternatively, ring P is absent and P4 is directly attached to ring M, provided that when ring P is absent, P4 and M4 are attached to the 1,2, 1,3, or 1,4 positions of ring M;
        one of P4 and M4 is -Z-A-B and the other -G1-G;
        G is a group of Formula IIa or IIb:
    
    






    
    
        in formula IIa, ring E is substituted with 1-2 Ra, provided that at least one Ra is ortho to the point of attachment of ring E;
        in formula IIb, ring D is substituted with 1-2 Ra, provided that at least one Ra is ortho to the point of attachment of ring D;
        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 0-2 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 0-2 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 0-1 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 0-2 carbonyl and 1-2 R and there are 0-3 ring double bonds;
        R is selected from H, C1-4 alkyl, 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(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), CH2CH2N(C1-3 alkyl)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;
        Ra is (CR8R9)0-3Rb(CR8R2b)0-4Rb0-1(CR8R9)0-4Rc;
        Rb is selected from O, C(O), C(O)NR3, C(O)N((CH2)1-3R3), S(O), S(O)2, S(O)2NR3, NR3, NR3C(O), NR3S(O)2, OC(O)NR3, NR3C(O)NR3, and SC(O)NR3;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)R3, CO2R3, C(O)NR3R3a, S(O)2NR3R3a, —CN, C3-10 carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-4 portion of Ra is absent, then Rc is selected from NR3C(O)R3, S(O)2NR3R3a, C3-10 carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that when the Ra is C(O)—NR*R* and NR*R* is a heterocyclic ring, then the heterocyclic ring is substituted with 1-2 R4;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        A is selected from: C3-10 carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4;
        B is selected from Y, X—Y, N(B1)C(O)C(R3R3g)1-4NB2B3, C(B5)═NB4, and
    
    






provided that Z and B are attached to different atoms on A and that the R4d shown is other than OH;

    
    
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —(CH2)0-2—C3-7 carbocycle substituted with 0-2 R4b, and —(CH2)0-2-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        B2 is selected from H, C1-6 alkyl substituted with 0-2 R4c, C(O)R2e, C(O)OR2d, C(O)NR2dR2d, C(O)NH(CH2)2NR2dR2d, SO2NR2dR2d, C(O)NHSO2—C1-4 alkyl, and S(O)pR5a;
        B3 is selected from H, C1-6 alkyl substituted with 0-2 R4c,
        —(CH2)0-2-3-6 membered carbocycle substituted with 0-2 R5, and a —(CH2)0-2-4-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R5;
        B4 is selected from H, SO2R3b, C(O)R3b, SO2NR3R3b, C(O)NR3R3b, OR2, SR2, —CN, and NO2;
        B5 is NR2R2f or CR3R2R2f;
        Q1 and Q2 are each N;
        alternatively, Q1 is CR3 and R4d is NR2R2a or NR3aB4, provided that when Q1 is CR3, then this R3 group optionally forms a ring with the R2 group of R4d, this ring is a 5-6 membered ring consisting of, in addition to the C—C—N shown, carbon atoms and from 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-1 R5;
        ring Q is a 5-8 membered ring consisting of, in addition to the
        Q1-CR4d=Q2 group shown, carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Y is selected from: CY1Y2R4a, NR3R3a, C(O)NR3R3a, C3-10 carbocycle substituted 0-2 R4 and 0-1 R4a, and, 3-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4 and 0-1 R4a;
        Y1 and Y2 are independently C1-4 alkyl substituted with 0-2 R4;
        X is absent or is selected from —(CR2R2a)1-4—, —CR2(CR2R2b)(CH2)t—, —C(O)—, —C(═NR1b)—, —CR2(NR1bR2)—, —CR2(OR2)—, —CR2(SR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —S(O)—, —S(O)2—, —SCR2R2a—, —S(O)CR2R2a—, —S(O)2CR2R2a—, —CR2R2aS(O)—, —CR2R2aS(O)2—, —S(O)2NR2CR2R2a—, —NR2S(O)2—, —CR2R2aNR2S(O)2—, —NR2S(O)2CR2R2a—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aNR2C(O)—, —NR2CR2R2a—, and —OCR2R2a—;
        G1 is 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)uNR3b(CR3R3a)w, (CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)w, (CR3R3a)uOC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)O(CR3R3a)w, (CR3R3a)uNR3bC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(S)NR3b(CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(O)(CR3R3a)w, (CR3R3a)uS(O)2(CR3R3a)w, (CR3R3a)uS(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bS(O)2(CR3R3a)w, (CR3R3a)uS(O)2NR3b(CR3R3a)w, (CR3R3a)uNR3bS(O)2NR3b(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)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uS(O)2NR3bC(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 and the right side of G1 is attached to ring G, provided that G1 does not form an 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)2NR3bC(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 and the right side of Z is attached to ring A, provided that Z does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        Z2 is selected from H, S(O)2NHR3b, C(O)R3b, C(O)NHR3b, C(O)OR3f, S(O)R3f, S(O)2R3f, C1-6 alkyl substituted with 0-2 R1a, C2-6 alkenyl substituted with 0-2 R1a, C2-6 alkynyl substituted with 0-2 R1a, —(C0-4 alkyl)-C3-10 carbocycle substituted with 0-3 R1a, and —(C0-4 alkyl)-5-10 membered heterocycle substituted with 0-3 R1a and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        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, —C2-6 alkenylene-R1b, —C2-6 alkynylene-R1b, and —(CR3R3a)r—C(═NR1b)NR3R1b, provided that R1a forms other than an N-halo, N—S, O—O, or N—CN bond;
        alternatively, when two R1a groups are attached to adjacent atoms, 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 R4b and 0-3 ring double bonds;
        R1b is selected from H, C1-3 alkyl, 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, C3-6 carbocycle substituted with 0-2 R4b, and 5-10 membered heterocycle substituted with 0-2 R4b and consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond and provided that S(O)pR2 forms other than S(O)2H or S(O)H;
        R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, —(CH2)r—C3-10 carbocycle 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)p, and substituted with 0-2 R4b;
        R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, —(CH2)r—C3-10 carbocycle 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)p, and substituted with 0-2 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and 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, C1-4 alkoxy substituted with 0-2 R4b, C1-6 alkyl substituted with 0-2 R4b, —(CH2)r—C3-10 carbocycle 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)p, and substituted with 0-2 R4b;
        R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle 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)p, and substituted with 0-2 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-6 alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-10 carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-10 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        alternatively, NR2dR2d forms a 5-10 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
        R2e, at each occurrence, is selected from H, R4c, C1-6 alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-10 carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-10 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f at each occurrence, is selected from H, CF3, C1-4 alkoxy substituted with 0-2 R4b, C1-6 alkyl substituted with 0-2 R4b, —(CH2)r—C3-10 carbocycle 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)p and substituted with 0-2 R4b;
        alternatively, CR2R2f forms a 5-8 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, NR2R2f forms a 5-8 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, when B4 is SO2R3b and B5 is NR2R2f, R3b and R2f combine to form a 5-8 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, when B4 is C(O)R3b and B5 is NR2R2, R3b and R2f combine to form a 5-8 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, when B5 is NR2R2f, B4 and R2f combine to form a 5-8 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b and the R2 group of NR2R2f, in addition to the groups recited below, is selected from SO2R3b, C(O)R3b, and —CN;
        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, R3 and 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 R3 and R3a are 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 H, C1-6 alkyl substituted with 0-2 R1a, C2-6 alkenyl substituted with 0-2 R1a, C2-6 alkynyl substituted with 0-2 R1a, —(C0-4 alkyl)-5-10 membered carbocycle substituted with 0-3 R1a, and —(C0-4 alkyl)-5-10 membered heterocycle substituted with 0-3 R1a and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        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, C1-4 alkyl-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, C1-6 alkyl substituted with 0-2 R1a, C2-6 alkenyl substituted with 0-2 R1a, C2-6 alkynyl substituted with 0-2 R1a, —(C0-4 alkyl)-5-10 membered carbocycle substituted with 0-3 R1a, and —(C0-4 alkyl)-5-10 membered heterocycle substituted with 0-3 R1a and 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: C1-6 alkyl substituted with 0-2 R1a, C2-6 alkenyl substituted with 0-2 R1a, C2-6 alkynyl substituted with 0-2 R1a, —(C0-4 alkyl)-5-10 membered carbocycle substituted with 0-3 R1a, and —(C0-4 alkyl)-5-10 membered heterocycle substituted with 0-3 R1a and 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, CR3R3g forms a cyclopropyl group;
        R4, at each occurrence, is selected from ═O, CHO, (CR3R3a)rOR2, (CR3R3a)rF, (CR3R3a)rCl, (CR3R3a)rBr, (CR3R3a)rI, C1-4 alkyl, (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)2R5)NR2R2a, (CR3R3a)rNR2C(═NR2)NR2R2a, (CR3R3a)rC(O)NR2C(═NR2)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rNR2SO2—C1-4 alkyl, (CR3R3a)rNR2SO2R5, (CR3R3a)rS(O)pR5a, (CR3R3a)r(CF2)rCF3, NHCH2R1b, OCH2R1b, SCH2R1b, NH(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)p and substituted with 0-1 R5;
        R4a is selected from C1-6 alkyl substituted with 0-2 R4c, C2-6 alkenyl substituted with 0-2 R4c, C2-6 alkynyl substituted with 0-2 R4c, —(CR3R3g)r—C5-10 membered carbocycle substituted with 0-3 R4c, —(CR3R3g)r-5-10 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CR3R3g)rCN, (CR3R3g)rC(═NR2d)NR2dR2d, (CR3R3g)rNR2dC(═NR2d)NR2dR2d, (CR3R3g)rNR2dC(R2e)(═NR2d), (CR3R3g)rNR2dR2d, (CR3R3g)rN(→O)R2dR2d, (CR3R3g)rOR2d, (CR3R3g)r—NR2dC(O)R2e, (CR3R3g)r—C(O)R2e, (CR3R3g)r—OC(O)R2e, (CR3R3g)r—C(O)NR2dR2d, (CR3R3g)r—C(O)OR2d, (CR3R3g)r—NR2dC(O)NR2dR2d, (CR3R3g)r—OC(O)NR2dR2d, (CR3R3g)r—NR2dC(O)OR2d, (CR3R3g)r—SO2NR2dR2d, (CR3R3g)r—NR2dSO2NR2dR2d, (CR3R3g)r—C(O)NR2dSO2R2d, (CR3R3g)r—NR2dSO2R2d, and (CR3R3g)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H and further provided that R4a is other than a hydroxamic acid;
        R4b, at each occurrence, is selected from H, ═O, (CH2)rOR3, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, (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—C1-4 alkyl, (CH2)rNR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (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, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, (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)NR2(CH2)2NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rC(═NR2)NR2R2a, (CR3R3a)rNR2C(═NR2)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rC(O)NR2SO2—C1-4 alkyl, (CR3R3a)rNR2SO2R5a, (CR3R3a)rC(O)NR2SO2R5a, (CR3R3a)rS(O)pR5a, (CF2)rCF3, (CR3R3a)rC3-10 carbocycle substituted with 0-2 R4b, and (CR3R3a)r4-10 membered heterocycle substituted with 0-2 R4b and consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        R4d, at each occurrence, is selected from H, (CR3R3a)rOR2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, C1-4 alkyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (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)rNR2SO2—C1-4 alkyl, (CR3R3a)rC(O)NHSO2—C1-4 alkyl, (CR3R3a)NR2SO2R5, (CR3R3a)rS(O)pR5a, (CR3R3a)r(CF2)rCF3, (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)p and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, C1-6 alkyl, ═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—C1-4 alkyl, (CH2)rNR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (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 C1-6 alkyl, (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 R5a does not form a S—N or S(O)p—C(O) bond;
        R6, at each occurrence, is selected from H, OH, (CH2)rOR2, halo, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
        R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkyl-C(O)—, C1-6 alkyl-O—, (CH2)n-phenyl, C1-4 alkyl-OC(O)—, C6-10 aryl-O—, C6-10 aryl-OC(O)—, C6-10 aryl-CH2—C(O)—, C1-4 alkyl-C(O)O—C1-4 alkyl-OC(O)—, C6-10 aryl-C(O)O—C1-4 alkyl-OC(O)—, C1-6 alkyl-NH2—C(O)—, phenyl-NH2—C(O)—, and phenyl-C1-4 alkyl-C(O)—;
        R8, at each occurrence, is selected from H, C1-6 alkyl, and (CH2)n-phenyl;
        alternatively, R7 and 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, C1-6 alkyl, 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; and
        t, at each occurrence, is selected from 0, 1, 2, and 3.
    
    


In a second embodiment, the present invention provides a novel compound of Formula II:




or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form 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 R1a and 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 P4 and M4 is -Z-A-B and the other -G1-G;
        G is a group of Formula IIa or IIb:
    
    






    
    
        in formula IIa, ring E is substituted with 1-2 Ra, provided that at least one Ra is ortho to the point of attachment of ring E;
        in formula IIb, ring D is substituted with 1-2 Ra, provided that at least one Ra is ortho to the point of attachment of ring D;
        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 0-2 R;
        alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 0-2 R;
        alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 0-2 R and 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 0-2 carbonyl and 1-2 R and there are 0-3 ring double bonds;
        R is selected from H, C1-4 alkyl, F, Cl, OH, OCH3, OCH2CH3, OCH(CH3)2, CN, C(═NH)NH2, C(═NH)NHOH, C(═NH)NHOCH3, NH2,
        NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, (CR8R9)tNR7R8, C(O)NR7R8, CH2C(O)NR7R8, S(O)pNR7R8, CH2S(O)pNR7R8, SO2R3, and OCF3;
        alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
        Ra is (CR8R9)0-1Rb(CR8R2b)0-4Rb0-1(CR8R9)0-1Rc;
        Rb is selected from O, C(O), C(O)NR3, C(O)N((CH2)2-3R3), S(O), S(O)2, S(O)2NR3, NR3, NR3C(O), and NR3S(O)2;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)R3, CO2R3, C(O)NR3R3a, S(O)2NR3R3a, —CN, C3-10 carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)R3, CO2R3, C(O)NR3R3a, S(O)2NR3R3a, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-1 portion of Ra is absent, then Rc is selected from NR3C(O)R3, S(O)2NR3R3a, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that when the Ra is C(O)—NR*R* and NR*R* is a heterocyclic ring, then the heterocyclic ring is substituted with 1-2 R4;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        A is selected from: C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4;
        B is selected from Y, X—Y, N(B1)C(O)C(R3R3g)NB2B3, N(B1)C(O)C(R3R3g)C(R3R3g)NB2B3,
    
    






provided that Z and B are attached to different atoms on A, the R4d shown is other than OH, and that the A-X—N moiety forms other than a N—N—N group;

    
    
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —(CH2)0-1—C3-7 carbocycle substituted with 0-2 R4b, and —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        B2 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, NR2dR2d, CH2—NR2dR2d, CH2CH2—NR2dR2d, C(O)R2e, C(O)NR2dR2d, SO2NR2dR2d, and S(O)pR5a;
        B3 is selected from H, C1-6 alkyl substituted with 0-1 R4c, —(CH2)0-1-3-6 membered carbocycle substituted with 0-1 R5, and a —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        B4 is selected from H, SO2R3b, C(O)R3b, SO2NR3R3b, C(O)NR3R3b, OR2, and —CN;
        B5 is NR2R2f or CR3R2R2f;
        ring Q is a 5-6 membered ring consisting of, in addition to the Q1-CR4d=Q2 group shown, carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Q1 and Q2 are each N;
        alternatively, Q1 is CR3 and R4d is NR2R2a or NR3aB4, provided that when Q1 is CR3, then this R3 group optionally forms a ring with the R2 group of R4d, this ring is a 5-6 membered ring consisting of, in addition to the C—C—N shown, carbon atoms and from 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-1 R5;
        Q4 is selected from C═O and SO2;
        ring Q3 is a 4-7 membered monocyclic or tricyclic ring consisting of, in addition to the N-Q4 group shown, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, wherein: 0-2 double bonds are present within the ring and the ring is substituted with 0-2 R4;
        alternatively, ring Q3 is a 4-7 membered ring to which another ring is fused, wherein: the 4-7 membered ring consists of, in addition to the shown amide group, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2 and 0-1 double bonds are present within the ring; the fusion ring is phenyl or a 5-6 membered heteroaromatic consisting of carbon atoms and 1-2 heteroatoms selected from NR4c, O, and S;
        ring Q3, which includes the 4-7 membered ring and the fusion ring, is substituted with 0-3 R4;
        ring Q5 is a C3-7 monocyclic carbocycle or 3-7 membered monocyclic heterocycle, wherein the carbocycle or heterocycle consists of: carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, the carbocycle or heterocycle further comprises 0-2 double bonds and 0-2 carbonyl groups, and the carbocycle or heterocycle is substituted with 0-2 R4;
        X is selected from —(CR2R2a)1-4—, —C(O)—, —C(═NR1c)—, —CR2(NR1bR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, —S(O)2—, —NR2S(O)2—, O, —CR2R2aO—, and —OCR2R2a—;
        Y is selected from: CY1Y2R4a, NR3R3a, and C(O)NR3R3a;
        Y1 and Y2 are independently C1-3 alkyl substituted with 0-2 R4;
        alternatively, Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-2 R4: cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
        Z is selected from a bond, CH2, CH2CH2, CH2O, OCH2, C(O), NH, CH2NH, NHCH2, CH2C(O), C(O)CH2, C(O)NH, NHC(O), NHC(O)CH2C(O)NH, S(O)2, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, wherein the right side of Z is attached to ring A, provided that Z does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3b, S(O)R3f, and S(O)2R3f;
        R1a, at each occurrence, is selected from H, —(CH2)r—R1b, —(CH(CH3))r—R1b, —(C(CH3)2)r—R1b, —O—(CR3R3a)r—R1b, —NR2—(CR3R3a)r—R1b, and —S—(CR3R3a)r—R1b, provided that R1a forms other than an N-halo, N—S, O—O, or N—CN bond;
        alternatively, when two R1a groups are attached to adjacent atoms, 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 R4b and 0-3 ring double bonds;
        R1b is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, —CN, —CHO, CF3, OR2, NR2R2a, C(O)R2b, CO2R2b, OC(O)R2, CO2R2a, S(O)pR2, NR2(CH2)rOR2, NR2C(O)R2b, NR2C(O)NHR2, NR2C(O)2R2a, OC(O)NR2R2a, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, a C5-6 carbocyclic-CH2-group substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2a, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and 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, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-6 carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        alternatively, NR2dR2d forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-6 carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f at each occurrence, is selected from H, CF3, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-1 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        alternatively, CR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, NR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, when B5 is NR2R2f, B4 and R2f combine to form a 5-6 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b and the R2 group of NR2R2f, in addition to the groups recited below, is selected from SO2R3b and C(O)R3b;
        R3, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
        R3a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
        alternatively, R3 and 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 and the nitrogen atom to which R3 and R3a are attached;
        R3b, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —(C0-1 alkyl)-5-6 membered carbocycle substituted with 0-1 R1a, and —(C0-1 alkyl)-5-6 membered heterocycle substituted with 0-1 R1a and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        R3c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
        R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2-phenyl, CH2CH2-phenyl, and C(═O)R3c;
        R4, at each occurrence, is selected from ═O, OR2, CH2OR2, (CH2)2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, NR2R2a, CH2NR2R2a, (CH2)2NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, S(O)pR5a, NR2SO2—C1-4 alkyl, NR2SO2R5, CF3, CF2CF3, 5-6 membered carbocycle substituted with 0-1 R5, and 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, and substituted with 0-1 R5;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2—C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, CH2NR3C(O)R3a, C(O)NR3R3a, CH2C(O)NR3R3a, NR3C(O)NR3R3a, CH2NR3C(O)NR3R3a, C(═NR3)NR3R3a, CH2C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, CH2NR3C(═NR3)NR3R3a, SO2NR3R3a, CH2SO2NR3R3a, NR3SO2NR3R3a, CH2NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, CH2NR3SO2—C1-4 alkyl, NR3SO2CF3, CH2NR3SO2CF3, NR3SO2-phenyl, CH2NR3SO2-phenyl, S(O)pCF3, CH2S(O)pCF3, S(O)p—C1-4 alkyl, CH2S(O)p—C1-4 alkyl, S(O)p-phenyl, CH2S(O)p-phenyl, CF3, and CH2—CF3;
        R4c, at each occurrence, is selected from ═O, (CR3R3a)rOR2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a)rCF3, C1-4 alkyl, C2-3 alkenyl, C2-3 alkynyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (CR3R3a)rN(→O)R2R2a, (CR3R3a)rC(O)R2c, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rNR2SO2R5a, (CR3R3a)rC(O)NR2SO2R5a, (CR3R3a)rS(O)pR5a, (CF2)rCF3, (CR3R3a)rC3-10 carbocycle 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)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, CH2OR2, OR2, C1-4 alkyl, CH2—CN, —CN, CH2NO2, NO2, CH2NR2R2a, NR2R2a, CH2—C(O)R2c, C(O)R2c, NR2C(O)R2b, (CH2)rC(O)NR2R2a, NR2C(O)NR2R2a, (CH2)rSO2NR2R2a, NR2SO2NR2R2a, NR2SO2R5, (CH2)rS(O)pR5a, CH2CF3, CF3, CH2-5-6 membered carbocycle substituted with 0-1 R5, 5-6 membered carbocycle substituted with 0-1 R5, a CH2-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5, and 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 and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3, F, Cl, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(═NOR3d), C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, CF3, 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 CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, CH2NR3C(O)R3a, C(O)NR3R3a, CH2C(O)NR3R3a, CF3, CF2CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6, provided that R5a does not form a S—N or S(O)p—C(O) bond; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, CN, NO2, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl.
    
    


In a third embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, wherein the compound is selected from:













    
    
        P4 is -G;
        M4 is -A-B;
        G is substituted with 1 Ra and is selected from the following group, wherein Ra is attached adjacent to the point of attachment of G:
    
    









    
    
        Ra is Rb(CR8R2b)0-4Rb0-1(CR8R9)0-1Rc;
        Rb is selected from C(O)NR3, S(O)2NR3, NR3C(O), and NR3S(O)2;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)NR3R3a, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-1 portion of Ra is absent, then Rc is selected from NR3C(O)R3, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        G1 is absent or is selected from (CR3R3a)1-3, CR3═CR3, (CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uO(CR3R3a)w, (CR3R3a)uNR3b(CR3R3a)w, (CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(O)(CR3R3a)w, (CR3R3a)uS(O)2(CR3R3a)w, (CR3R3a)uS(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bS(O)2(CR3R3a)w, and (CR3R3a)uS(O)2NR3b(CR3R3a)w, wherein u+w total 0, 1, or 2, wherein the right side of G1 is attached to ring G, provided that G1 does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R4; cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —(CH2)0-1—C5-6 carbocycle substituted with 0-2 R4b, and —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        B2 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(O)R2e, C(O)NR2dR2d, SO2NR2dR2d, and S(O)pR5a;
        B3 is selected from H, C1-6 alkyl substituted with 0-1 R4c, —(CH2)0-1-3-6 membered carbocycle substituted with 0-1 R5, and a —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        B4 is selected from H, SO2R3b and OR2;
        B5 is NR2R2f;
        ring Q is a 5-6 membered ring consisting of, in addition to the N—CR4d═N group shown, carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Q4 is selected from C═O and SO2;
        ring Q3 is a 5-7 membered ring consisting of, in addition to the N-Q4 group shown, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, wherein: 0-2 double bonds are present within the ring and the ring is substituted with 0-2 R4a;
        alternatively, ring Q3 is a 5-7 membered ring to which another ring is fused, wherein: the 5-7 membered ring consists of, in addition to the shown amide group, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, and 0-1 double bonds are present within the ring; the fusion ring is phenyl or a 5-6 membered heteroaromatic consisting of carbon atoms and 1-2 heteroatoms selected from NR4c, O, and S;
        ring Q3, which includes the 5-7 membered ring and the fusion ring, is substituted with 0-3 R4a;
        ring Q5, is a C3-6 monocyclic carbocycle or 5-6 membered monocyclic heterocycle, wherein the carobocycle or heterocycle consists of carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, the carbocycle or heterocycle further comprises 0-1 double bonds and 0-1 carbonyl groups, and the carbocycle or heterocycle is substituted with 0-2 R4;
        X is selected from —(CR2R2a)1-2—, —C(═NR1b)—, —C(O)—, —S(O)2—, —NR2S(O)2—, —NR2S(O)2—, —NR2C(O)—, —C(O)NR2—, —NR2C(O)CR2R2a—, —NR2C(O)NR2—, NR2, —NR2CR2R2a—, —CR2R2aNR2—, O, —OCR2R2a—, and —CR2R2aO—;
        Y is selected from: CY1Y2R4a, NR3R3a, and C(O)NR3R3a;
        Y1 and y are independently C1-2 alkyl substituted with 0-2 R4;
        alternatively, Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-1 R4: cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
        R1a is selected from H, R1b, CH(CH3)R1b, C(CH3)2R1b, CH2R1b, and CH2CH2R1b, provided that R1a forms other than an N-halo, N—S, or N—CN bond;
        alternatively, when two R1a groups are attached to adjacent atoms, together with the atoms to which they are attached they form 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, this ring being substituted with 0-2 R4b and 0-3 ring double bonds;
        R1b is selected from H, CH3, CH2CH3, F, Cl, Br, —CN, —CHO, CF3, OR2, NR2R2a, C(O)R2b, CO2R2b, OC(O)R2, CO2R2a, S(O)pR2, NR2(CH2)rOR2, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, NR2SO2R2, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-2 R4b, a benzyl substituted with 0-2 R4b, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2a, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-2 R4b, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and 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, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-2 R4b, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2c, at each occurrence, is selected from CF3, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-2 R4b, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CR3R3a)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CR3R3a)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CR3R3a)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CR3R3a)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, and benzyl;
        alternatively, NR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, B4 and R2f combine to form a 5-6 membered ring consisting of: carbon atoms and 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b and the R2 group of NR2R2f, in addition to the groups recited below, can be SO2R3b;
        R3b, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
        R4, at each occurrence, is selected from H, ═O, CH2OR2, (CH2)2OR2, OR2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —CN, NO2, NR2R2a, CH2NR2R2a, (CH2)2NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, CF3, and CF2CF3;
        R4a is selected from —(CR3R3g)r-5-6 membered carbocycle substituted with 0-3 R4c, —(CR3R3g)r-5-6 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CR3R3g)rNR2dR2d, (CR3R3g)rN(→O)R2dR2d, (CR3R3g)rOR2d, (CR3R3g)r—NR2dC(O)R2e, (CR3R3g)r—C(O)R2e, (CR3R3g)r—OC(O)R2e, (CR3R3g)r—C(O)NR2dR2d, (CR3R3g)r—C(O)OR2d, (CR3R3g)r—NR2dC(O)NR2dR2d, (CR3R3g)r—NR2dC(O)OR2d, (CR3R3g)r—SO2NR2dR2d, (CR3R3g)r—NR2dSO2R2d, and (CR3R3g)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2—C(O)R3, C(O)OR3c, CH2—C(O)OR3c, NR3C(O)R3a, CH2NR3C(O)R3a, C(O)NR3R3a, CH2—C(O)NR3R3a, SO2NR3R3a, CH2SO2NR3R3a, NR3SO2—C1-4 alkyl, CH2NR3SO2—C1-4 alkyl, NR3SO2-phenyl, CH2NR3SO2-phenyl, S(O)pCF3, CH2S(O)pCF3, S(O)p—C1-4 alkyl, CH2S(O)p—C1-4 alkyl, S(O)p-phenyl, CH2S(O)p-phenyl, and CF3;
        R4c, at each occurrence, is selected from ═O, OR2, (CR3R3a)OR2, F, (CR3R3a)F, Br, (CR3R3a)Br, Cl, (CR3R3a)Cl, CF3, (CR3R3a)CF3, C2-3 alkenyl, C2-3 alkynyl, C1-4 alkyl, —CN, (CR3R3a)CN, NO2, (CR3R3a)NO2, NR2R2a, (CR3R3a)NR2R2a, N(→O)R2R2a, (CR3R3a)N(O)R2R2a, C(O)R2c, (CR3R3a)C(O)R2c, NR2C(O)R2b, (CR3R3a)NR2C(O)R2b, C(O)NR2R2a, (CR3R3a)C(O)NR2R2a, NR2C(O)NR2R2a, (CR3R3a)NR2C(O)NR2R2a, SO2NR2R2a, (CR3R3a)SO2NR2R2a, NR2SO2NR2R2a, (CR3R3a)NR2SO2NR2R2a, NR2SO2R5a, (CR3R3a)NR2SO2R5a, S(O)pR5a, (CR3R3a)S(O)pR5a, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 R4b, (CR3R3a)C3-10 carbocycle substituted with 0-2 R4b, 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b, and (CR3R3a)-5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, CH2OR2, OR2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —CN, NO2, CH2NR2R2a, NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, NR2SO2R5, SO2NR2R2a, 6-membered carbocycle substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-2 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, SO2NR2R2a, and NR2SO2C1-4 alkyl.
    
    


In a fourth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the third embodiment, wherein:

    
    
        G is substituted with 1 Ra, wherein Ra is attached adjacent to the point of attachment of G:
        Ra is Rb(CR8R2b)0-3Rb0-1Rc;
        Rb is C(O)NR3;
        Rc is selected from H, OR3, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-1 portion of Ra is absent, then Rc is selected from C5-10 carbocycle substituted with 0-2 R4 and 5-11 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        G1 is absent or is selected from CH2, CH2CH2, CH2O, OCH2, NH, CH2NH, NHCH2, CH2C(O), C(O)CH2, C(O)NH, NHC(O), CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, wherein the right side of G1 is attached to ring G, provided that G1 does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        A is selected from cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4;
        B is selected from Y, N(B1)C(O)C(R3R3g)NB2B3,
    
    






provided that Z and B are attached to different atoms on A, the R4d shown is other than OH, and that the A-X—N moiety forms other than a N—N—N group;

    
    
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
        B2 is selected from H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
        B3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, C2-5 alkyl substituted with 1 R4c, —(CH2)0-1-3-6 membered carbocycle substituted with 0-1 R5, and a —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        B4 is selected from H, SO2R3b, and OR2;
        B5 is NR2R2f;
        ring Q is a 5-6 membered ring consisting of, in addition to the N—CR4d═N group shown, carbon atoms and 0-1 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Q4 is selected from C═O and SO2;
        ring Q3 is a 6-7 membered ring consisting of, in addition to the N-Q4 group shown, carbon atoms and 0-1 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, wherein: 0-2 double bonds are present within the ring and the ring is substituted with 0-2 R4;
        alternatively, ring Q3 is a 5-7 membered ring to which another ring is fused, wherein: the 5-7 membered ring consists of, in addition to the shown amide group, carbon atoms and 0-1 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, and 0-1 double bonds are present within the ring; the fusion ring is phenyl;
        ring Q3, which includes the 5-7 membered ring and the fusion ring, is substituted with 0-2 R4;
        ring Q5 is substituted with 0-1 R4 and is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentanonyl, cyclohexyl, cyclohexanonyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydrofuranyl, and tetrahydropyranyl;
        X is selected from CH2, C(O), —S(O)2—, —NHC(O)—, —C(O)NH—, —CH2NH—, O, and —CH2O—;
        Y is selected from N(CH3)2, C(O)(CH3)2, C(CH3)2R4a and C(CH2CH3)2R4a;
        alternatively, Y is selected from phenyl, pyridyl, pyrrolidino, N-pyrrolidino-carbonyl, morpholino, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a and 0-1 R4;
        R1a, at each occurrence, is selected from H, R1b, CH(CH3)R1b, C(CH3)2R1b, and CH2R1b, provided that R1a forms other than an N-halo, N—S, or N—CN bond;
        R1b is selected from CH3, CH2CH3, F, Cl, Br, —CN, CF3, OR2, NR2R2a, C(O)R2b, CO2R2b, CO2R2a, S(O)pR2, C(O)NR2R2a, SO2NR2R2a, NR2SO2R2, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 R4b and 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 OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CH2)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CH2)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CH2)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CH2)-5-6 membered heterocycle and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f, at each occurrence, is selected from H, CH3, CH2CH3, OCH3, and benzyl;
        alternatively, NR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-1 R4b;
        alternatively, B4 and R2f combine to form a 5 membered ring consisting of: carbon atoms and 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R and the R2 group of NR2R2f, in addition to the groups recited below, can be SO2R3b;
        R3b, at each occurrence, is selected from H and CH3;
        R4, at each occurrence, is selected from H, ═O, OH, OR2, CH2OR2, (CH2)2OR2, F, Br, Cl, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, NR2R2a, CH2NR2R2a, (CH2)2NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, CF3, and CF2CF3;
        R4a is selected from —(CR3R3g)r-5-6 membered carbocycle substituted with 0-3 R4c, —(CR3R3g)r-5-6 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CR3R3g)rNR2dR2d, (CR3R3g)rN(→O)R2dR2d, (CR3R3g)rOR2d, (CR3R3g)r—C(O)NR2dR2d, (CR3R3g)r—NR2dC(O)R2e, (CR3R3g)r—C(O)R2e, (CR3R3g)r—NR2dC(O)NR2dR2d, (CR3R3g)r—NR2dC(O)OR2d, (CR3R3g)r—NR2dSO2R2d, and (CR3R3g)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)p—C1-4 alkyl, S(O)p-phenyl, and CF3;
        R4c, at each occurrence, is selected from ═O, OR2, CH2OR2, F, Br, Cl, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, C2-3 alkenyl, C2-3 alkynyl, —CN, NO2, NR2R2a, CH2NR2R2a, N(→O)R2R2a, CH2N(→O)R2R2a, C(O)R2c, CH2C(O)R2c, NR2C(O)R2b, CH2NR2C(O)R2b, C(O)NR2R2a, CH2C(O)NR2R2a, SO2NR2R2a, CH2SO2NR2R2a, NR2SO2R5a, CH2NR2SO2R5a, S(O)pR5a, CH2S(O)pR5a, CF3, CF2CF3, C3-6 carbocycle substituted with 0-2 R4b, (CH2)C3-6 carbocycle substituted with 0-2 R4b, 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b, and (CH2)-5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, CH2OR2, OR2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, CH2NR2R2a, NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, NR2SO2R5, phenyl substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1 heteroatom selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)p—C1-4 alkyl, S(O)p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, and SO2NR2R2a.
    
    


In a fifth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the fourth embodiment, wherein:

    
    
        A is selected from the group: cyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;
        B is selected from Y, N(B1)C(O)C(R3R3g)NB2B3,
    
    






provided that Z and B are attached to different atoms on A and that the R4d shown is other than OH;

    
    
        B1 is selected from H, CH3, CH2CH3, and CH2CH2CH3;
        B2 is selected from H, CH3, and CH2CH3;
        B3 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, C(CH3)3, CH(CH3)CH2CH(CH3)2, CH2CH2OH, CH(CH3)CH2OH, CH(phenyl)CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and CH2-cyclopropyl;
    
    






is attached to a different atom on A than M and is selected from the group:











    
    
        ring Q5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, 2-cyclopentanonyl, cyclohexyl, 2-cyclohexanonyl, pyrrolidinyl (attached to A and R4a at the 2-position), pyrrolidinyl (attached to A and R4a at the 3-position), 2-pyrrolidinonyl (attached to A and R4a at the 3-position), piperidinyl (attached to A and R4a at the 4-position), 4-piperdinonyl (attached to A and R4a at the 3-position), tetrahydrofuranyl, and tetrahydropyranyl (attached to A and R4a at the 4-position);
        Y is selected from N(CH3)2, C(O)(CH3)2, C(CH3)2R4a and C(CH2CH3)2R4a;
        alternatively, Y is selected from phenyl, pyridyl, 1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a;
        R1a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH2F, CH2Cl, Br, CH2Br, —CN, CH2CN, CF3, CH2CF3, OCH3, CH2OH, C(CH3)2OH, CH2OCH3, NH2, CH2NH2, NHCH3, CH2NHCH3, N(CH3)2, CH2N(CH3)2, CO2H, COCH3, CO2CH3, CH2CO2CH3, SCH3, CH2SCH3, S(O)CH3, CH2S(O)CH3, S(O)2CH3, CH2S(O)2CH3, C(O)NH2, CH2C(O)NH2, SO2NH2, CH2SO2NH2, NHSO2CH3, CH2NHSO2CH3, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N-oxide, imidazol-1-yl, CH2-imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N,N-dimethylaminomethyl-oxazol-2-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH2-1,2,3,4-tetrazol-1-yl, and CH2-1,2,3,4-tetrazol-5-yl, provided that R1a forms other than an N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2a, at each occurrence, is selected from H, CH3, and CH2CH3;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 R4b and 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 OCH3, OCH2CH3, CH3, and CH2CH3;
        R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, and CH2CH3;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f, at each occurrence, is selected from H, CH3, CH2CH3, and OCH3;
        alternatively, NR2R2f forms a ring selected from morpholine, piperazine, piperidine, and pyrrolidine;
        R4, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, and C(CH3)3;
        R4a is selected from —(CH2)r-5-6 membered carbocycle substituted with 0-3 R4c, —(CH2)r-5-6 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CH2)rNR2dR2d, (CH2)rN(→O)R2dR2d, (CH2)rOR2d, (CH2)r—C(O)NR2dR2d, (CH2)r—NR2dC(O)R2e, (CH2)r—C(O)R2e, (CH2)r—NR2dC(O)NR2dR2d, (CH2)r—NR2dC(O)OR2d, (CH2)r—NR2dSO2R2d, and (CH2)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2-phenyl, S(O)2CH3, S(O)2-phenyl, and CF3;
        R4c, at each occurrence, is selected from ═O, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C2-3 alkenyl, C2-3 alkynyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3, CH2OCH(CH3)2, F, Br, Cl, CF3, NR2R2a, CH2NR2R2a, N(→O)R2R2a, CH2N(→O)R2R2a, C(O)R2c, CH2C(O)R2c, NR2C(O)R2b, CH2NR2C(O)R2b, C(O)NR2R2a, CH2C(O)NR2R2a, SO2NR2R2a, CH2SO2NR2R2a, NR2SO2R5a, CH2NR2SO2R5a, S(O)pR5a, CH2S(O)pR5a, CF3, cyclopropyl substituted with 0-1 R4b, cyclobutyl substituted with 0-1 R4b, cyclopentyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, —CH2-cyclopropyl substituted with 0-1 R4b, —CH2-cyclobutyl substituted with 0-1 R4b, —CH2-cyclopentyl substituted with 0-1 R4b, benzyl substituted with 0-2 R4b, 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b, and (CH2)-5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, OCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NR2R2a, NR2C(O)R2b, NR2SO2R5, phenyl, 2-oxo-pyrrolidinyl, and 2-oxo-piperidinyl;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, OR3, CH2OR3, F, Cl, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)2—CH3, S(O)2-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, and SO2NR2R2a.
    
    


In a sixth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the fourth embodiment, wherein:

    
    
        A is selected from the group: phenyl, 2-pyridyl, 2-pyrimidyl, and 2-F-phenyl, wherein B is substituted at the 4-position of A;
        B is selected from:
    
    









    
    
        R2d, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl, substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R4a is selected from NR2dR2d, CH2NR2dR2d, CH2CH2NR2dR2d, N(→O)R2dR2d, CH2N(→O)R2dR2d, CH2OR2d, C(O)R2e, C(O)NR2dR2d, CH2C(O)NR2dR2d, NR2dC(O)R2e, CH2NR2dC(O)R2e, NR2dC(O)NR2dR2d, CH2NR2dC(O)NR2dR2d, NR2dC(O)OR2d, CH2NR2dC(O)OR2d, NR2dSO2R2d, CH2NR2dSO2R2d, S(O)pR2d, CH2S(O)pR2d, 5-6 membered carbocycle substituted with 0-2 R4c, —(CH2)-5-6 membered carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CH2)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p provided that S(O)pR2d forms other than S(O)2H or S(O)H; and
        R4c is selected from ═O, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH═CH2, CH≡CH, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3, CH2OCH(CH3)2, F, Br, Cl, CF3, NR2R2a, CH2NR2R2a, C(O)R2c, CH2C(O)R2c, NR2C(O)R2b, CH2NR2C(O)R2b, C(O)NR2R2a, CH2C(O)NR2R2a, SO2NR2R2a, CH2SO2NR2R2a, NR2SO2R5a, CH2NR2SO2R5a, S(O)pR5a, and CH2S(O)pR5a.
    
    


In a seventh embodiment, the present invention provides a novel compound of




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

    
    
        P4 is -G;
        M4 is -A-B;
        A-B is selected from:
    
    
























    
    
        R2d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2, CH2CCH, CH2CH2OH, CH2C(O)NH2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, cyclopentyl, and thiazolyl;
        R2e, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2, CH2-cyclopropyl, cyclopropyl, and cyclopentyl;
        R4a is substituted with 0-2 R4c and selected from morpholine, 1,1-dioxo-thiomorpholine, dihydropyridine, piperidine, piperazine, pyrrolidine, imidazole, imidazoline, imidazolidine, oxazoline, and thiazoline; and
        R4c is selected from ═O, OH, OCH3, and CH3.
    
    


In an eighth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, wherein the compound is selected from the group: Examples 3-30, 32-33, 37-44, 61, 109-118, 135-146, 148-151, 154-165, 168-192, 195-199, 204-205, 207-213, 215, 217, 219-232, 235-237, 240-241, and, 244-255.
In a ninth embodiment, the present invention provides a novel compound, wherein the compound is of Formula IIIa, IIIb, or IIIc:




or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, wherein;

    
    
        ring M, including M1, M2, and, if present, M3, is phenyl or a 3-10 membered carbocyclic or 4-10 membered heterocyclic ring consisting of: carbon atoms and 1-4 heteroatoms selected from O, S(O)p, N, and NZ2;
        ring M is substituted with 0-3 R1a and 0-2 carbonyl groups, and there are 0-3 ring double bonds;
        one of P4 and M4 is -Z-A-B and the other -G1-G;
        G is a group of Formula IIa or IIb:
    
    






    
    
        in formula IIa, ring E is substituted with 1-2 Ra, provided that at least one Ra is ortho to the point of attachment of ring E;
        in formula IIb, ring D is substituted with 1-2 Ra, provided that at least one Ra is ortho to the point of attachment of ring D;
        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 0-2 R;
        alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 0-2 R;
        alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with 0-2 R and 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 0-2 carbonyl and 1-2 R and there are 0-3 ring double bonds;
        R is selected from H, C1-4 alkyl, F, Cl, OH, OCH3, OCH2CH3, OCH(CH3)2, CN, C(═NH)NH2, C(═NH)NHOH, C(═NH)NHOCH3, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, (CR8R9)tNR7R8, C(O)NR7R8, CH2C(O)NR7R8, S(O)pNR7R8, CH2S(O)pNR7R8, SO2R3, and OCF3;
        alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
        Ra is (CR8R9)0-1Rb(CR8R2b)0-4Rb0-1(CR8R9)0-1Rc;
        Rb is selected from O, C(O), C(O)NR3, C(O)N((CH2)2-3R3), S(O), S(O)2, S(O)2NR3, NR3, NR3C(O), and NR3S(O)2;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)R3, CO2R3, C(O)NR3R3a, S(O)2NR3R3a, —CN, C3-10 carbocycle substituted with 0-2 R4, and 5-12 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)R3, CO2R3, C(O)NR3R3a, S(O)2NR3R3a, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-1 portion of Ra is absent, then Rc is selected from NR3C(O)R3, S(O)2NR3R3a, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that when the Ra is C(O)—NR*R* and NR*R* is a heterocyclic ring, then the heterocyclic ring is substituted with 1-2 R4;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        A is selected from: C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4;
        B is selected from Y, X—Y, N(B1)C(O)C(R3R3g)NB2B3, N(B1)C(O)C(R3R3g)C(R3R3g)NB2B3,
    
    






provided that Z and B are attached to different atoms on A, the R4d shown is other than OH, and that the A-X—N moiety forms other than a N—N—N group;

    
    
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —(CH2)0-1—C3-7 carbocycle substituted with 0-2 R4b, and —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        B2 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, NR2dR2d, CH2—NR2dR2d, CH2CH2—NR2dR2d, C(O)R2e, C(O)NR2dR2d, SO2NR2dR2d, and S(O)pR5a;
        B3 is selected from H, C1-6 alkyl substituted with 0-1 R4c, —(CH2)0-1-3-6 membered carbocycle substituted with 0-1 R5, and a —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        B4 is selected from H, SO2R3b, C(O)R3b, SO2NR3R3b, C(O)NR3R3b, OR2, and —CN;
        B5 is NR2R2f or CR3R2R2f;
        ring Q is a 5-6 membered ring consisting of, in addition to the Q1-CR4d=Q2 group shown, carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Q1 and Q2 are each N;
        alternatively, Q1 is CR3 and R4d is NR2R2a or NR3aB4, provided that when Q1 is CR3, then this R3 group optionally forms a ring with the R2 group of R4d, this ring is a 5-6 membered ring consisting of, in addition to the C—C—N shown, carbon atoms and from 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-1 R5;
        Q4 is selected from C═O and SO2;
        ring Q3 is a 4-7 membered monocyclic or tricyclic ring consisting of, in addition to the N-Q4 group shown, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, wherein: 0-2 double bonds are present within the ring and the ring is substituted with 0-2 R4;
        alternatively, ring Q3 is a 4-7 membered ring to which another ring is fused, wherein: the 4-7 membered ring consists of, in addition to the shown amide group, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2 and 0-1 double bonds are present within the ring; the fusion ring is phenyl or a 5-6 membered heteroaromatic consisting of carbon atoms and 1-2 heteroatoms selected from NR4c, O, and S;
        ring Q3, which includes the 4-7 membered ring and the fusion ring, is substituted with 0-3 R4;
        ring Q5 is a C3-7 monocyclic carbocycle or 3-7 membered monocyclic heterocycle, wherein the carbocycle or heterocycle consists of: carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, the carbocycle or heterocycle further comprises 0-2 double bonds and 0-2 carbonyl groups, and the carbocycle or heterocycle is substituted with 0-2 R4;
        X is selected from —(CR2R2a)1-4—, —C(O)—, C(═NR1c)—, —CR2(NR1bR2)—, —C(O)CR2R2a—, —CR2R2aC(O), —C(O)NR2—, —NR2C(O)—, —C(O)NR2CR2R2a—, —NR2C(O)CR2R2a—, —CR2R2aC(O)NR2—, —CR2R2aNR2C(O)—, —NR2C(O)NR2—, —NR2—, —NR2CR2R2a—, —CR2R2aNR2—, —S(O)2—, —NR2S(O)2—, O, —CR2R2aO—, and —OCR2R2a—;
        Y is selected from: CY1Y2R4a, NR3R3a, and C(O)NR3R3a;
        Y1 and Y2 are independently C1-3 alkyl substituted with 0-2 R4;
        alternatively, Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-2 R4: cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
        Z is selected from a bond, CH2, CH2CH2, CH2O, OCH2, C(O), NH, CH2NH, NHCH2, CH2C(O), C(O)CH2, C(O)NH, NHC(O), NHC(O)CH2C(O)NH, S(O)2, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, wherein the right side of Z is attached to ring A, provided that Z does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        Z2 is selected from H, C1-4 alkyl, phenyl, benzyl, C(O)R3b, S(O)R3f, and S(O)2R3f;
        R1a, at each occurrence, is selected from H, —(CH2)r—R1b, —(CH(CH3))r—R1b, —(C(CH3)2)r—R1b, —O—(CR3R3a)r—R1b, —NR2—(CR3R3a)r—R1b, and —S—(CR3R3a)r—R1b, provided that R1a forms other than an N-halo, N—S, O—O, or N—CN bond;
        alternatively, when two R1a groups are attached to adjacent atoms, 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 R4b and 0-3 ring double bonds;
        R1b is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, —CN, —CHO, CF3, OR2, NR2R2a, C(O)R2b, CO2R2b, OC(O)R2, CO2R2a, S(O)pR2, NR2(CH2)rOR2, NR2C(O)R2b, NR2C(O)NHR2, NR2C(O)2R2a, OC(O)NR2R2a, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, a C5-6 carbocyclic-CH2-group substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2a, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and 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, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-2 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-6 carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        alternatively, NR2dR2d forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and consisting of: 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, —(CR3R3a)r—C3-6 carbocycle substituted with 0-2 R4c, and —(CR3R3a)r-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f, at each occurrence, is selected from H, CF3, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl substituted with 0-1 R4b, C5-6 carbocycle substituted with 0-2 R4b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        alternatively, CR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, NR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, when B5 is NR2R2f, B4 and R2f combine to form a 5-6 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b and the R2 group of NR2R2f, in addition to the groups recited below, is selected from SO2R3b and C(O)R3b;
        R3, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
        R3a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
        alternatively, R3 and 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 and the nitrogen atom to which R3 and R3a are attached;
        R3b, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —(C0-1 alkyl)-5-6 membered carbocycle substituted with 0-1 R1a, and —(C0-1 alkyl)-5-6 membered heterocycle substituted with 0-1 R1a and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        R3c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl, and phenyl;
        R3d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2-phenyl, CH2CH2-phenyl, and C(═O)R3c;
        R4, at each occurrence, is selected from ═O, OR2, CH2OR2, (CH2)2OR2, F, Cl, Br, I, C1-4 alkyl, —CN, NO2, NR2R2a, CH2NR2R2a, (CH2)2NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, S(O)pR5a, NR2SO2—C1-4 alkyl, NR2SO2R5, CF3, CF2CF3, 5-6 membered carbocycle substituted with 0-1 R5, and 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, and substituted with 0-1 R5;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2—C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, CH2NR3C(O)R3a, C(O)NR3R3a, CH2C(O)NR3R3a, NR3C(O)NR3R3a, CH2NR3C(O)NR3R3a, C(═NR3)NR3R3a, CH2C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, CH2NR3C(═NR3)NR3R3a, SO2NR3R3a, CH2SO2NR3R3a, NR3SO2NR3R3a, CH2NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, CH2NR3SO2—C1-4 alkyl, NR3SO2CF3, CH2NR3SO2CF3, NR3SO2-phenyl, CH2NR3SO2-phenyl, S(O)pCF3, CH2S(O)pCF3, S(O)p—C1-4 alkyl, CH2S(O)p—C1-4 alkyl, S(O)p-phenyl, CH2S(O)p-phenyl, CF3, and CH2—CF3;
        R4c, at each occurrence, is selected from ═O, (CR3R3a)rOR2, (CR3R3a)rF, (CR3R3a)rBr, (CR3R3a)rCl, (CR3R3a)rCF3, C1-4 alkyl, C2-3 alkenyl, C2-3 alkynyl, (CR3R3a)rCN, (CR3R3a)rNO2, (CR3R3a)rNR2R2a, (CR3R3a)rN(→O)R2R2a, (CR3R3a)rC(O)R2c, (CR3R3a)rNR2C(O)R2b, (CR3R3a)rC(O)NR2R2a, (CR3R3a)rNR2C(O)NR2R2a, (CR3R3a)rSO2NR2R2a, (CR3R3a)rNR2SO2NR2R2a, (CR3R3a)rNR2SO2R5a, (CR3R3a)rC(O)NR2SO2R5a, (CR3R3a)rS(O)pR5a, (CF2)rCF3, (CR3R3a)rC3-10 carbocycle 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)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, CH2OR2, OR2, C1-4 alkyl, CH2—CN, —CN, CH2NO2, NO2, CH2NR2R2a, NR2R2a, CH2—C(O)R2c, C(O)R2c, NR2C(O)R2b, (CH2)rC(O)NR2R2a, NR2C(O)NR2R2a, (CH2)rSO2NR2R2a, NR2SO2NR2R2a, NR2SO2R5, (CH2)rS(O)pR5a, CH2CF3, CF3, CH2-5-6 membered carbocycle substituted with 0-1 R5, 5-6 membered carbocycle substituted with 0-1 R5, a CH2-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5, and 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 and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3, F, Cl, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(═NOR3d), C(═NR3)NR3R3a, NR3C(═NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, CF3, 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 CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, OR3, CH2OR3, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, CH2NR3C(O)R3a, C(O)NR3R3a, CH2C(O)NR3R3a, CF3, CF2CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6, provided that R5a does not form a S—N or S(O)p—C(O) bond; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, CN, NO2, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, C(═NH)NH2, NHC(═NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl.
    
    


In a tenth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, wherein the compound is selected from:




    
    
        G is substituted with 1 Ra and is selected from the following group, wherein Ra is attached adjacent to the point of attachment of G:
    
    









    
    
        Ra is R(CR8R2b)0-4Rb0-1(CR8R9)0-1Rc;
        Rb is selected from C(O)NR3, S(O)2NR3, NR3C(O), and NR3S(O)2;
        Rc is selected from H, OR3, NR3C(O)R3, C(O)NR3R3a, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-1 portion of Ra is absent, then Rc is selected from NR3C(O)R3, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        G1 is absent or is selected from (CR3R3a)1-3, CR3═CR3, (CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uO(CR3R3a)w, (CR3R3a)uNR3b(CR3R3a)w, (CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uS(CR3R3a)w, (CR3R3a)uS(O)(CR3R3a)w, (CR3R3a)uS(O)2(CR3R3a)w, (CR3R3a)uS(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bS(O)2(CR3R3a)w, and (CR3R3a)uS(O)2NR3b(CR3R3a)w, wherein u+w total 0, 1, or 2, wherein the right side of G1 is attached to ring G, provided that G1 does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        A is selected from one of the following carbocyclic and heterocyclic groups which are substituted with 0-2 R4; cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —(CH2)0-1—C5-6 carbocycle substituted with 0-2 R4b, and —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        B2 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(O)R2e, C(O)NR2dR2d, SO2NR2dR2d, and S(O)pR5a;
        B3 is selected from H, C1-6 alkyl substituted with 0-1 R4c, —(CH2)0-1-3-6 membered carbocycle substituted with 0-1 R5, and a —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        B4 is selected from H, SO2R3b and OR2;
        B5 is NR2R2f;
        ring Q is a 5-6 membered ring consisting of, in addition to the N—CR4d═N group shown, carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Q4 is selected from C═O and SO2;
        ring Q3 is a 5-7 membered ring consisting of, in addition to the N-Q4 group shown, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, wherein: 0-2 double bonds are present within the ring and the ring is substituted with 0-2 R4a;
        alternatively, ring Q3 is a 5-7 membered ring to which another ring is fused, wherein: the 5-7 membered ring consists of, in addition to the shown amide group, carbon atoms and 0-2 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, and 0-1 double bonds are present within the ring; the fusion ring is phenyl or a 5-6 membered heteroaromatic consisting of carbon atoms and 1-2 heteroatoms selected from NR4c, O, and S;
        ring Q3, which includes the 5-7 membered ring and the fusion ring, is substituted with 0-3 R4a;
        ring Q5, is a C3-6 monocyclic carbocycle or 5-6 membered monocyclic heterocycle, wherein the carobocycle or heterocycle consists of carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)p, the carbocycle or heterocycle further comprises 0-1 double bonds and 0-1 carbonyl groups, and the carbocycle or heterocycle is substituted with 0-2 R4;
        X is selected from —(CR2R2a)1-2—, —C(═NR1)—, —C(O)—, —S(O)2—, —NR2S(O)2—, —NR2S(O)2—, —NR2C(O)—, —C(O)NR2—, —NR2C(O)CR2R2a—, —NR2C(O)NR2—, NR2, —NR2CR2R2a—, —CR2R2aNR2—, O, —OCR2R2a—, and —CR2R2aO—;
        Y is selected from: CY1Y2R4a, NR3R3a, and C(O)NR3R3a;
        Y1 and Y2 are independently C1-2 alkyl substituted with 0-2 R4;
        alternatively, Y is selected from one of the following carbocyclic and heterocycles that are substituted with 1 R4a and 0-1 R4: cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzimidazolone, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
        R1a is selected from H, R1b, CH(CH3)R1b, C(CH3)2R1b, CH2R1b, and CH2CH2R1b, provided that R1a forms other than an N-halo, N—S, or N—CN bond;
        alternatively, when two R1a groups are attached to adjacent atoms, together with the atoms to which they are attached they form 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, this ring being substituted with 0-2 R4b and 0-3 ring double bonds;
        R1b is selected from H, CH3, CH2CH3, F, Cl, Br, —CN, —CHO, CF3, OR2, NR2R2a, C(O)R2b, CO2R2b, OC(O)R2, CO2R2a, S(O)pR2, NR2(CH2)rOR2, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, NR2SO2R2, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-2 R4b, a benzyl substituted with 0-2 R4b, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2a, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-2 R4b, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and 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, C1-4 alkoxy, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-2 R4b, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2c, at each occurrence, is selected from CF3, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-2 R4b, phenyl substituted with 0-2 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CR3R3a)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CR3R3a)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CR3R3a)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CR3R3a)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, and benzyl;
        alternatively, NR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b;
        alternatively, B4 and R2f combine to form a 5-6 membered ring consisting of: carbon atoms and 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b and the R2 group of NR2R2f, in addition to the groups recited below, can be SO2R3b;
        R3b, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
        R4, at each occurrence, is selected from H, ═O, CH2OR2, (CH2)2OR2, OR2, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —CN, NO2, NR2R2a, CH2NR2R2a, (CH2)2NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, CF3, and CF2CF3;
        R4a is selected from —(CR3R3g)r-5-6 membered carbocycle substituted with 0-3 R4c, —(CR3R3g)r-5-6 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CR3R3g)rNR2dR2d, (CR3R3g)rN(→O)R2dR2d, (CR3R3g)rOR2d, (CR3R3g)r—NR2dC(O)R2e, (CR3R3g)r—C(O)R2e, (CR3R3g)r—OC(O)R2e, (CR3R3g)r—C(O)NR2dR2d, (CR3R3g)r—C(O)OR2d, (CR3R3g)r—NR2dC(O)NR2dR2d, (CR3R3g)r—NR2dC(O)OR2d, (CR3R3g)r—SO2NR2dR2d, (CR3R3g)r—NR2dSO2R2d, and (CR3R3g)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2—C(O)OR3c, NR3C(O)R3a, CH2NR3C(O)R3a, C(O)NR3R3a, CH2—C(O)NR3R3a, SO2NR3R3a, CH2SO2NR3R3a, NR3SO2—C1-4 alkyl, CH2NR3SO2—C1-4 alkyl, NR3SO2-phenyl, CH2NR3SO2-phenyl, S(O)pCF3, CH2S(O)pCF3, S(O)p—C1-4 alkyl, CH2S(O)p—C1-4 alkyl, S(O)p-phenyl, CH2S(O)p-phenyl, and CF3;
        R4c, at each occurrence, is selected from ═O, OR2, (CR3R3a)OR2, F, (CR3R3a)F, Br, (CR3R3a)Br, Cl, (CR3R3a)Cl, CF3, (CR3R3a)CF3, C2-3 alkenyl, C2-3 alkynyl, C1-4 alkyl, —CN, (CR3R3a)CN, NO2, (CR3R3a)NO2, NR2R2a, (CR3R3a)NR2R2a, N(→O)R2R2a, (CR3R3a)N(→O)R2R2a, C(O)R2c, (CR3R3a)C(O)R2c, NR2C(O)R2b, (CR3R3a)NR2C(O)R2b, C(O)NR2R2a, (CR3R3a)C(O)NR2R2a, NR2C(O)NR2R2a, (CR3R3a)NR2C(O)NR2R2a, SO2NR2R2a, (CR3R3a)SO2NR2R2a, NR2SO2NR2R2a, (CR3R3a)NR2SO2NR2R2a, NR2SO2R5a, (CR3R3a)NR2SO2R5a, S(O)pR5a, (CR3R3a)S(O)pR5a, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 R4b, (CR3R3a)C3-10 carbocycle substituted with 0-2 R4b, 5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b, and (CR3R3a)-5-10 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, CH2OR2, OR2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, —CN, NO2, CH2NR2R2a, NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, NR2SO2R5, SO2NR2R2a, 6 membered carbocycle substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-2 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, CH2C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)p—C1-4 alkyl, S(O)p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, SO2NR2R2a, and NR2SO2C1-4 alkyl.
    
    


In an eleventh embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the tenth embodiment, wherein:

    
    
        G is substituted with 1 Ra wherein Ra is attached adjacent to the point of attachment of G:
        Ra is Rb(CR8R2b)0-3Rb0-1Rc;
        Rb is C(O)NR3;
        Rc is selected from H, OR3, C5-10 carbocycle substituted with 0-2 R4, and 5-10 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        provided that when the (CR8R2b)0-4Rb0-1(CR8R9)0-1 portion of Ra is absent, then Rc is selected from C5-10 carbocycle substituted with 0-2 R4 and 5-11 membered heterocycle substituted with 0-2 R4 and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
        further provided that the (CR8R2b)0-4Rb0-1(CR8R9)0-4Rc portion of Ra is other than (CR8R2b)0-3-unsubstituted-phenyl or (CR8R9)0-3-unsubstituted-phenyl;
        G1 is absent or is selected from CH2, CH2CH2, CH2O, OCH2, NH, CH2NH, NHCH2, CH2C(O), C(O)CH2, C(O)NH, NHC(O), CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, wherein the right side of G1 is attached to ring G, provided that G1 does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        A is selected from cyclohexyl, indolinyl, piperidinyl, piperazinyl, phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R4;
        B is selected from Y, N(B1)C(O)C(R3R3g)NB2B3,
    
    






provided that Z and B are attached to different atoms on A, the R4d shown is other than OH, and that the A-X—N moiety forms other than a N—N—N group;

    
    
        B1 is selected from H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
        B2 is selected from H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2;
        B3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, C2-5 alkyl substituted with 1 R4c, —(CH2)0-1-3-6 membered carbocycle substituted with 0-1 R5, and a —(CH2)0-1-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        B4 is selected from H, SO2R3b, and OR2;
        B5 is NR2R2f;
        ring Q is a 5-6 membered ring consisting of, in addition to the
        N—CR4d═N group shown, carbon atoms and 0-1 heteroatoms selected from N, O, and S(O)p, and the ring is substituted with an additional 0-2 R4d;
        Q4 is selected from C═O and SO2;
        ring Q3 is a 6-7 membered ring consisting of, in addition to the N-Q4 group shown, carbon atoms and 0-1 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, wherein: 0-2 double bonds are present within the ring and the ring is substituted with 0-2 R4;
        alternatively, ring Q3 is a 5-7 membered ring to which another ring is fused, wherein: the 5-7 membered ring consists of, in addition to the shown amide group, carbon atoms and 0-1 heteroatoms selected from NR4c, O, S, S(O), and S(O)2, and 0-1 double bonds are present within the ring; the fusion ring is phenyl;
        ring Q3, which includes the 5-7 membered ring and the fusion ring, is substituted with 0-2 R4;
        ring Q5 is substituted with 0-1 R4 and is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentanonyl, cyclohexyl, cyclohexanonyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydrofuranyl, and tetrahydropyranyl;
        X is selected from CH2, C(O), —S(O)2—, —NHC(O)—, —C(O)NH—, —CH2NH—, O, and —CH2O—;
        Y is selected from N(CH3)2, C(O)(CH3)2, C(CH3)2R4a and C(CH2CH3)2R4a;
        alternatively, Y is selected from phenyl, pyridyl, pyrrolidino, N-pyrrolidino-carbonyl, morpholino, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a and 0-1 R4;
        R1a, at each occurrence, is selected from H, R1b, CH(CH3)R1b, C(CH3)2R1b, and CH2R1b, provided that R1a forms other than an N-halo, N—S, or N—CN bond;
        R1b is selected from CH3, CH2CH3, F, Cl, Br, —CN, CF3, OR2, NR2R2a, C(O)R2b, CO2R2b, CO2R2a, S(O)pR2, C(O)NR2R2a, SO2NR2R2a, NR2SO2R2, and 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4b, provided that R1b forms other than an O—O, N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 R4b and 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 OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, benzyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, and 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CH2)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CH2)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 carbocycle substituted with 0-2 R4c, —(CH2)—C3-6 carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CH2)-5-6 membered heterocycle and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f at each occurrence, is selected from H, CH3, CH2CH3, OCH3, and benzyl;
        alternatively, NR2R2f forms a 5-6 membered ring consisting of: carbon atoms and 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-1 R4b;
        alternatively, B4 and R2f combine to form a 5 membered ring consisting of: carbon atoms and 0-1 additional heteroatoms selected from N, O, and S(O)p, and this ring is substituted with 0-2 R4b and the R2 group of NR2R2f, in addition to the groups recited below, can be SO2R3b;
        R3b, at each occurrence, is selected from H and CH3;
        R4, at each occurrence, is selected from H, ═O, OH, OR2, CH2OR2, (CH2)2OR2, F, Br, Cl, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, NR2R2a, CH2NR2R2a, (CH2)2NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, CF3, and CF2CF3;
        R4a is selected from —(CR3R3g)r-5-6 membered carbocycle substituted with 0-3 R4c, —(CR3R3g)r-5-6 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CR3R3g)rNR2dR2d, (CR3R3g)rN(→O)R2dR2d, (CR3R3g)rOR2d, (CR3R3g)r—C(O)NR2dR2d, (CR3R3g)r—NR2dC(O)R2e, (CR3R3g)r—C(O)R2e, (CR3R3g)r—NR2dC(O)NR2dR2d, (CR3R3g)r—NR2dC(O)OR2d, (CR3R3g)r—NR2dSO2R2d, and (CR3R3g)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)p—C1-4 alkyl, S(O)p-phenyl, and CF3;
        R4c, at each occurrence, is selected from ═O, OR2, CH2OR2, F, Br, Cl, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, C2-3 alkenyl, C2-3 alkynyl, —CN, NO2, NR2R2a, CH2NR2R2a, N(→O)R2R2a, CH2N(→O)R2R2a, C(O)R2c, CH2C(O)R2c, NR2C(O)R2b, CH2NR2C(O)R2b, C(O)NR2R2a, CH2C(O)NR2R2a, SO2NR2R2a, CH2SO2NR2R2a, NR2SO2R5a, CH2NR2SO2R5a, S(O)pR5a, CH2S(O)pR5a, CF3, CF2CF3, C3-6 carbocycle substituted with 0-2 R4b, (CH2)C3-6 carbocycle substituted with 0-2 R4b, 5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b, and (CH2)-5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, CH2OR2, OR2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, CH2NR2R2a, NR2R2a, C(O)R2c, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, NR2SO2R5, phenyl substituted with 0-1 R5, and a 5-6 membered heterocycle consisting of: carbon atoms and 1 heteroatom selected from the group consisting of N, O, and S(O)p and substituted with 0-1 R5;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OR3, CH2OR3, F, Cl, —CN, NO2, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)p—C1-4 alkyl, S(O)p-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, —CN, NO2, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, and SO2NR2R2a.
    
    


In a twelfth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the eleventh embodiment, wherein:

    
    
        G1 is absent or is selected from CH2NH, NHCH2, CH2C(O), C(O)CH2, C(O)NH, NHC(O), NHC(O)NH, CH2S(O)2, S(O)2(CH2), SO2NH, and NHSO2, wherein the right side of G1 is attached to ring G, provided that G1 does not form a N—S, NCH2N, NCH2O, or NCH2S bond with either group to which it is attached;
        A is selected from the group: cyclohexyl, indolinyl, phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;
        B is selected from Y, N(B1)C(O)C(R3R3g)NB2B3,
    
    






provided that Z and B are attached to different atoms on A and that the R4d shown is other than OH;

    
    
        B1 is selected from H, CH3, CH2CH3, and CH2CH2CH3;
        B2 is selected from H, CH3, and CH2CH3;
        B3 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, C(CH3)3, CH(CH3)CH2CH(CH3)2, CH2CH2OH, CH(CH3)CH2OH, CH(phenyl)CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and CH2-cyclopropyl;
    
    






is attached to a different atom on A than M and is selected from the group:











    
    
        ring Q5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, 2-cyclopentanonyl, cyclohexyl, 2-cyclohexanonyl, pyrrolidinyl (attached to A and R4a at the 2-position), pyrrolidinyl (attached to A and R4a at the 3-position), 2-pyrrolidinonyl (attached to A and R4a at the 3-position), piperidinyl (attached to A and R4a at the 4-position), 4-piperdinonyl (attached to A and R4a at the 3-position), tetrahydrofuranyl, and tetrahydropyranyl (attached to A and R4a at the 4-position);
        Y is selected from N(CH3)2, C(O)(CH3)2, C(CH3)2R4a and C(CH2CH3)2R4a;
        alternatively, Y is selected from phenyl, pyridyl, 1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a;
        R1a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH2F, CH2Cl, Br, CH2Br, —CN, CH2CN, CF3, CH2CF3, OCH3, CH2OH, C(CH3)2OH, CH2OCH3, NH2, CH2NH2, NHCH3, CH2NHCH3, N(CH3)2, CH2N(CH3)2, CO2H, COCH3, CO2CH3, CH2CO2CH3, SCH3, CH2SCH3, S(O)CH3, CH2S(O)CH3, S(O)2CH3, CH2S(O)2CH3, C(O)NH2, CH2C(O)NH2, SO2NH2, CH2SO2NH2, NHSO2CH3, CH2NHSO2CH3, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl-N-oxide, pyridin-3-yl-N-oxide, pyridin-4-yl-N-oxide, imidazol-1-yl, CH2-imidazol-1-yl, 4-methyl-oxazol-2-yl, 4-N,N-dimethylaminomethyl-oxazol-2-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-5-yl, CH2-1,2,3,4-tetrazol-1-yl, and CH2-1,2,3,4-tetrazol-5-yl, provided that R1a forms other than an N-halo, N—S, or N—CN bond;
        R2, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, phenyl substituted with 0-1 R4b, benzyl substituted with 0-1 R4b, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 R4b;
        R2a, at each occurrence, is selected from H, CH3, and CH2CH3;
        alternatively, NR2R2a forms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-1 R4b and 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 OCH3, OCH2CH3, CH3, and CH2CH3;
        R2c, at each occurrence, is selected from OH, OCH3, OCH2CH3, CH3, and CH2CH3;
        R2d, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, R4c, C1-4 alkyl substituted with 0-2 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R2f, at each occurrence, is selected from H, CH3, CH2CH3, and OCH3;
        alternatively, NR2R2f forms a ring selected from morpholine, piperazine, piperidine, and pyrrolidine;
        R4, at each occurrence, is selected from H, ═O, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, and C(CH3)3;
        R4a is selected from —(CH2)r-5-6 membered carbocycle substituted with 0-3 R4c, —(CH2)r-5-6 membered heterocycle substituted with 0-3 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, (CH2)rNR2dR2d, (CH2)rN(→O)R2dR2d, (CH2)rOR2d, (CH2)r—C(O)NR2dR2d, (CH2)r—NR2dC(O)R2e, (CH2)r—C(O)R2e, (CH2)r—NR2dC(O)NR2dR2d, (CH2)r—NR2dC(O)OR2d, (CH2)r—NR2dSO2R2d, and (CH2)r—S(O)pR2d, provided that S(O)pR2d forms other than S(O)2H or S(O)H;
        R4b, at each occurrence, is selected from H, ═O, OR3, CH2OR3, F, Cl, CH3, CH2CH3, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2-phenyl, S(O)2CH3, S(O)2-phenyl, and CF3;
        R4c, at each occurrence, is selected from ═O, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C2-3 alkenyl, C2-3 alkynyl, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3, CH2OCH(CH3)2, F, Br, Cl, CF3, NR2R2a, CH2NR2R2a, N(→O)R2R2a, CH2N(→O)R2R2a, C(O)R2c, CH2C(O)R2c, NR2C(O)R2b, CH2NR2C(O)R2b, C(O)NR2R2a, CH2C(O)NR2R2a, SO2NR2R2a, CH2SO2NR2R2a, NR2SO2R5a, CH2NR2SO2R5a, S(O)pR5a, CH2S(O)pR5a, CF3, cyclopropyl substituted with 0-1 R4b, cyclobutyl substituted with 0-1 R4b, cyclopentyl substituted with 0-1 R4b, phenyl substituted with 0-1 R4b, —CH2-cyclopropyl substituted with 0-1 R4b, —CH2-cyclobutyl substituted with 0-1 R4b, —CH2-cyclopentyl substituted with 0-1 R4b, benzyl substituted with 0-2 R4b, 5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b, and (CH2)-5-6 membered aromatic heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 R4b;
        R4d, at each occurrence, is selected from H, OCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, NR2R2a, NR2C(O)R2b, NR2SO2R5, phenyl, 2-oxo-pyrrolidinyl, and 2-oxo-piperidinyl;
        R5, at each occurrence, is selected from H, ═O, CH3, CH2CH3, OR3, CH2OR3, F, Cl, NR3R3a, CH2NR3R3a, C(O)R3, C(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, SO2NR3R3a, NR3SO2—C1-4 alkyl, NR3SO2-phenyl, S(O)2—CH3, S(O)2-phenyl, CF3, phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6; and
        R6, at each occurrence, is selected from H, OH, OR2, F, Cl, CH3, CH2CH3, NR2R2a, CH2NR2R2a, C(O)R2b, CH2C(O)R2b, NR2C(O)R2b, and SO2NR2R2a.
    
    


In a thirteenth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the twelfth embodiment, wherein:

    
    
        A is selected from the group: indolinyl, phenyl, 2-pyridyl, 2-pyrimidyl, and 2-F-phenyl, wherein B is substituted at the 4-position of A, except when A is indolinyl, then B is substituted at the 6-position of A;
        B is selected from:
    
    









    
    
        R2d, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl substituted with 0-2 R4c, and a 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2d forms other than a N-halo, N—C-halo, S(O)p-halo, O-halo, N—S, S—N, S(O)p—S(O)p, S—O, O—N, O—S, or O—O moiety;
        R2e, at each occurrence, is selected from H, C1-4 alkyl substituted with 0-1 R4c, C3-6 cycloalkyl substituted with 0-2 R4c, phenyl, substituted with 0-2 R4c, and 5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2e forms other than a C(O)-halo or C(O)—S(O)p moiety;
        R4a is selected from NR2dR2d, CH2NR2dR2d, CH2CH2NR2dR2d, N(→O)R2dR2d, CH2N(→O)R2dR2d, CH2OR2d, C(O)R2e, C(O)NR2dR2d, CH2C(O)NR2dR2d, NR2dC(O)R2e, CH2NR2dC(O)R2e, NR2dC(O)NR2dR2d, CH2NR2dC(O)NR2dR2d, NR2dC(O)OR2d, CH2NR2dC(O)OR2d, NR2dSO2R2d, CH2NR2dSO2R2d, S(O)pR2d, CH2S(O)pR2d, 5-6 membered carbocycle substituted with 0-2 R4c, —(CH2)-5-6 membered carbocycle substituted with 0-2 R4c, 5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and —(CH2)-5-6 membered heterocycle substituted with 0-2 R4c and consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p provided that S(O)pR2d forms other than S(O)2H or S(O)H; and
        R4c is selected from ═O, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH═CH2, CH≡CH, CH2OH, CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3, CH2OCH(CH3)2, F, Br, Cl, CF3, NR2R2a, CH2NR2R2a, C(O)R2c, CH2C(O)R2c, NR2C(O)R2b, CH2NR2C(O)R2b, C(O)NR2R2a, CH2C(O)NR2R2a, SO2NR2R2a, CH2SO2NR2R2a, NR2SO2R5a, CH2NR2SO2R5a, S(O)pR5a, and CH2S(O)pR5a.
    
    


In a fourteenth embodiment, the present invention provides a novel compound or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof, within the scope of the thirteenth embodiment, wherein the compound is selected from:




    
    
        P4 is -G;
        A-B is selected from:
    
    
























    
    
        R2d, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2, CH2CCH, CH2CH2OH, CH2C(O)NH2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, cyclopentyl, and thiazolyl;
        R2e, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2, CH2-cyclopropyl, cyclopropyl, and cyclopentyl;
        R4a is substituted with 0-2 R4c and selected from morpholine, 1,1-dioxo-thiomorpholine, dihydropyridine, piperidine, piperazine, pyrrolidine, imidazole, imidazoline, imidazolidine, oxazoline, and thiazoline; and
        R4c is selected from ═O, OH, OCH3, and CH3.
    
    


In a fifteenth embodiment, the present invention provides a novel compound, wherein the compound is selected from the group: Examples 62-102 and 105-106 or a stereoisomer or pharmaceutically acceptable salt, solvate, or prodrug form thereof.
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, solvate, or prodrug 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, solvate, or prodrug 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, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (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 agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase.
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
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.
Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole. Preferably, the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.
The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N). The present invention, in general, does not cover groups such as N-halo, S(O)H, and SO2H.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative.
As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-6 alkyl, is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-6 alkoxy, is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Alkenyl” 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. C2-6 alkenyl is intended to include C2, C3, C4, C5, and C6 alkenyl groups. “Alkynyl” is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. C2-6 Alkynyl is intended to include C2, C3, C4, C5, and C6 alkynyl groups.
“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, “carbocycle” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic 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). When the term “carbocycle” is used, it is intended to include “aryl”. 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 heteroatoms 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. When the term “heterocycle” is used, it is intended to include heteroaryl.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p 1445, the disclosure of which is hereby incorporated by reference.
In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

    
    
        a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K. Widder, et. al. (Academic Press, 1985);
        b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H. Bundgaard, at pp. 113-191 (1991);
        c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992);
        d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and
        e) N. Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).
    
    


Preparation of prodrugs is well known in the art and described in, for example, Medicinal Chemistry: Principles and Practice, ed. F. D. King, The Royal Society of Chemistry, Cambridge, UK, 1994, which is incorporated herein by reference in its entirety.
Radiolabelled compounds of the present invention, i.e., wherein one or more of the atoms described are replaced by a radioactive isotope of that atom (e.g., C replaced by 13C or by 14C; and isotopes of hydrogen include tritium and deuterium), are also provided herein. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
“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.
The present invention further includes compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.
A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference in its entirety.
Synthesis
All references cited herein are hereby incorporated in their entirety by reference.
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. Those skilled in the art of organic synthesis understand 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.
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 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, 1999).
The synthesis of compounds of the present invention that involves the usage of intermediate A-B is accomplished via standard methods known to those skilled in the art.
Construction of compounds with general structure G-G1-P-M-Z-A-B can be performed in two directions: 1) From G to G-G1-P-M (or a derivative of P-M) then to G-G1-P-M-Z-A-B or 2) From A-B to P-M-Z-A-B (or a derivative of P-M) then to G-G1-P-M-Z-A-B. The general route that involves this type of methodology is outlined in Scheme 1. During the synthesis of these compounds, protecting groups to prevent cross-reaction during the coupling conditions optionally protect the functional groups of the substituents. Examples of suitable blocking groups and their uses are described in “The Peptides: Analysis, Synthesis, Biology”, Academic Press, Vol. 3 (Groii, et. al. Eds., 1981). Functional group transformations and coupling reactions that can be used to prepare compounds of the present invention are described in “Advanced Organic Chemistry: Reaction, Mechanism, and Structure” (March, et. al. fourth Ed.) and “Comprehensive Organic Transformations” (Larock, second Ed.).




Compounds of the present invention where B is Y—R4a (provided that A and R4a are attached to the same carbon atom in Y and Y is C3-C7 cycloalkyl) can be prepared as shown in Scheme 2. Commercially available 4-nitrophenylacetonitrile (or properly protected 4-aminophenylacetonitrile) can be used as the starting material. Alkylation with NaH, t-BuOK, NaNH2, n-BuLi, s-BuLi, NaOEt, aq NaOH, etc. as the base, and X—(CH2)n—Y (X and Y can be Cl, Br, I, OMs, OTs, or +S(CH3)2 and n=2-6) as the alkylating reagent can afford the cycloalkyl intermediate 1. Hydrolysis of the nitrile group, followed by reduction of the ester group can provide the alcohol 2. Oxidation of 2, then reductive amination with NHR2dR2d can provide 3. Reduction of the nitro group or deprotection of the amino group can produce the A-B precursor 4, which can be coupled with 5 using standard coupling conditions as described in Scheme 1 to provide 6. When one of the R2d groups is H, 6 can react with acid chlorides, carbamoyl chlorides, sulfonyl chlorides, and isocyanates to provide compounds of the invention with structures 7, 8, 9, and 10. Alternatively, alcohol 2 can react with alkyl halides and amines to form compounds of the invention with structures 11 and 12. Alcohol 2 can also be transformed into a halide or its equivalents (X═Cl, Br, I, OMs, or OTs), followed by alkylation with a variety of alkylating reagents to afford compounds of the invention with structures 13, 14, and 15.







Other compounds of the present invention where Y is a cycloalkyl derivative can be prepared using commercially available 1-phenylcycloalkylcarboxylic acids (or 1-phenylcycloalkylcarbonitriles) as the starting materials as illustrated in Scheme 3. Nitration, followed by reduction of the NO2 group and protection of the acid group can provide the A-B precursor 16, which can be coupled with 5 using standard coupling conditions to provide 17.
Alternatively, iodination can provide the desired para-substituted compound 18, which can in turn be transformed to the amine 16 via Buchwald palladium-catalyzed amination (Tetrahedron Lett. 1997, 38, 6367-6370) and to the acid 19 via paladium-catalyzed carboxylation (CO, Pd(OAc)2, dppf). Additional A-B intermediates can be synthesized by chemical manipulation of the amino and carboxylic acid functionality in 16 and 19, respectively. Compound 19 can be homologated via the Arndt-Eistert methodology to afford other A-B intermediates in 20. Alternatively, the acid functionality in 19 can be reduced to the alcohol that in turn can be converted to a variety of A-B intermediates 20 by procedures known to those skilled in the art. Further elaboration of these intermediates using the methods described above and by those known in the art should provide compounds of the present invention.




Other compounds of the present invention where Y is a cycloalkyl derivative can be prepared using organometalic reagents 21 (Zn, Mg, etc.) as starting materials as shown in Scheme 4. Reaction of 21 with properly substituted cycloalkyl halides 22 (X═Cl, Br, I, OMs, OTs, etc.) using Pd(dba)2/1,2-bis(diphenylphosphino)ethane (dppe) or NiCl2(PPh3)2 as the catalyst system can provide intermediate 23. Alternatively, Grignard reaction of 21 with cycloalkyl ketones can provide intermediate 24. Further elaboration of 23 and 24 using the methods described above and by those known in the art should provide compounds of the present invention.




Compounds of the present invention where Y is a pyrrolidine or piperidine derivative can be prepared as shown in Scheme 5. Phenylcyanoacetate can be alkylated with X—(CH2)n—Cl (X and Y═Br, I, OMs, OTs, etc. and n=2-3) to provide chloronitrile 25, which can be reduced to the corresponding primary amine, followed by cyclization in refluxing EtOH to form 3-pyrrolidine or 3-piperdine derivatives 26. Alkylation or reductive amination can provide N-substituted intermediate 27. Further elaboration using the methods described above and by those known in the art should provide compounds of the present invention.




Compounds of the present invention where Y is a pyrrolidine derivative can also be prepared as illustrated in Scheme 6. The Grignard reaction of 1-substituted 4-piperidone 28 with an appropriate arylmagnesium halide followed by dehydration should give tetrahydropyridine derivative 29. Epoxidation followed by rearrangement with heating in boron trifluroride etherate (Chem. Pharm. Bull. 1980, 28(5), 1387-1393) can provide pyrrolidine aldehyde 30. Alternatively, radical cyclization of alkyl azide 31 (Tetrahedron Lett. 1997, 38, 3915-3918) can provide pyrrolidine intermediate 32. Further elaboration of these intermediates using the methods described above and by those known in the art should provide compounds of the present invention.




Compounds of the present invention where Y is a 4-piperidine derivative can be prepared using 2-aryl acetonitriles 33 as starting materials as shown in Scheme 7. Dialkylation of 33 with bromoacetaldehyde dimethyl acetal, followed by hydrolysis of the acetals and reductive amination should give the 4-aryl-4-cyanopiperidine 34. Further elaboration of these intermediates using the methods described above and by those known in the art should provide compounds of the present invention.




Compounds of the present invention where Y is a 4-tetrahydrfuran derivative can be prepared using diol 35 as the starting material as illustrated in Scheme 8. Cyclization of 35 with HBr should give 4-aryl-4-substituted tetrahydrofuran 36. Further elaboration using the methods described above and by those known in the art should provide compounds of the present invention.




Compounds of the present invention where Y is a 4-tetrahydropyran derivative can be prepared using 2-aryl acetonitriles 33 as starting materials as shown in Scheme 9. Alkylation of 33 with di-2-chloroethyl ether should give the 4-aryl-4-cyanotetrahydropyran 37. Further elaboration using the methods described above and by those known in the art should provide compounds of the present invention.




Compounds of the present invention where Y is a lactam derivative can be prepared using intermediate 38 as the starting material as shown in Scheme 10. Reduction of the nitro or nitrile group can provide the primary amine 39, which can be coupled intramolecularly with the acid or ester to form the lactam 40. Further elaboration using the methods described above and by those known in the art should provide compounds of the present invention.




Aminopyridyl, aminopyrimidyl, cyclohexyl, and piperidinyl A-B analogs (see structures in Scheme 11) can be prepared using routes similar to those of Schemes 2-10 and by those known in the art. These intermediates can then be further manipulated to compounds of the present invention via procedures previously described.




Compounds of the present invention (Scheme 1) where R4a is CH2CH2NR2dR2d or CH2CONR2dR2d can be prepared as outlined in Scheme 12 and via standard methods known to those skilled in the art. The ester or nitrile intermediates 41 illustrated in Scheme 12 can be subjected to alkylation conditions, followed by other manipulations as described in Schemes 2-10 to form 42. Homologation of intermediates 42 with TMSCHN2 as the reagent can afford 43. Further elaboration of 43 to form 44 and compounds of the present invention can be achieved using the methods described above and by those known in the art.




Compounds of the present invention where R4a is NR2dR2d can be prepared as outlined in Scheme 13 and via standard methods known to those skilled in the art. The acid intermediates 42 illustrated in Scheme 13 can undergo Curtius rearrangement with DPPA in CH2Cl2 followed by heating in t-BuOH to afford Boc-protected cyclopropylamine intermediates 45. Alkylation of 45 with R2d—I and NaH in THF followed by manipulations described previously should give amines 46. Reductive amination of 46 with aqueous formaldehyde and NaBH3CN in CH3CN can afford the methyl alkyl amine analogues. On the other hand, alkylation with dibromides using K2CO3 as the base can afford tertiary or cyclic amines, respectively. Further elaboration of 46 to form compounds of the present invention can be achieved using the methods described above and by those known in the art.




Schemes 2-13 describe how to make the A-B moieties of the present invention and how to couple them to prepare compounds of the present invention. Schemes 2-13 describe A-B wherein B is Y—R4a and Y is a cycloalkyl or heterocyclyl. Compounds of the present invention wherein Y is CY1Y2 can be made analogously to the cycloalkyl/heterocyclyl compounds of Schemes 2-13. For example, in Scheme 2, instead of intermediate 1 being a cycloalkyl intermediate, it can be Y1Y2 disubstituted intermediate. This intermediate could be made by a number of methods including di-substituting the starting 4-nitrophenyl-acetonitrile by reaction with a base and a Y1-leaving group and a Y2-leaving group. One of ordinary skill in the art would recognize that other routes to the Y1Y2-disubstituted intermediates are available. The remainder of the chemistry shown in Scheme 2 will then follow. In Scheme 3, instead of use the starting 1-phenylcycloalkylcarboxylic acids or 1-phenylcycloalkylcarbonitriles, one could use the corresponding Y1Y2-disubstituted intermediates. As in Scheme 2, these intermediates could be prepared by di-substituting a phenylcarboxylic acid or phenylcarbonitrile. One of ordinary skill in the art would recognize that other routes to these types of Y1Y2 disubstituted intermediate are also available. The remainder of the chemistry shown in Scheme 3 will then follow.
Compounds of the present invention wherein Y is N(B1)C(O)C(R3R3g)1-4NB2B3 can be made as described in Schemes 14-16. Scheme 14 describes the syntheses of an A-B intermediate via Buchwald Ullmann coupling reaction (J. Am. Chem. Soc. 2001, 123, 7727) using CuI and 1,2-cyclohexyldiamine or 1,10-phenanthroline as the catalyst.




Alternatively, the A-B intermediates containing amides NH(B1)C(O)C(R3R3g)1-4NB2B3 can also be prepared from readily available anilines as shown in Scheme 15.




Aminopyridyl, aminopyrimidyl, indonyl, cyclohexyl, and piperidinyl A-B analogs (see structures in Scheme 16) can be prepared using routes similar to those of Schemes 14-15 and by those known in the art. These intermediates can then be further manipulated to compounds of the present invention via procedures previously described.




Compounds of the present invention wherein B is a cyclic phenyl amidino derivative can be prepared following the general procedure outlined in Scheme 17. Boc-protection of the aniline followed by alkylation with chloroiodo-alkane can provide the Boc-protected intermediate. Azide displacement followed by reduction and deprotection can afford the diamine compound. Reaction with ethylformate, etc. can generate the corresponding A-B intermediate. Compounds wherein R4a is H, alkyl, or ether can then be obtained using the methods described previously and by those known in the art.




The diamino intermediate from Scheme 17 can also be transformed to an alcohol intermediate followed by treatment with POCl3, POBr3, Tf2O, or an alkylating agent. Further manipulations of these versatile intermediates to the compounds of the present invention can be achieved using the methods described in Scheme 18 and by those known in the art.




The guanidino derivative from Scheme 18 can be converted to a number of compounds of the present invention by techniques known to those of skill in the art of organic synthesis, as outlined in Scheme 19.




Using the methodologies outlined above, other compounds of the present invention can be obtained as shown in Scheme 20 by functional manipulations and cyclization techniques known to those of skill in the art of organic synthesis.




Phenylamidino-sulfonyl and -carbonyl compounds of the present invention can be obtained from the readily available amidino compounds shown in Scheme 21 below.




The chemistry leading to the compounds of the present invention described above can be implemented at various stages of the synthetic process. Those knowledgeable in the art may decide to prepare various sulfonyl, carbonylamidino, or suitably protected cyclic amidino intermediates and couple these via known techniques to various templates described herein to afford 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.
The functionalized G moiety of the present invention can be commercially available or 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 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, WO02/00651, WO02/102380, WO02/094197, USPA 2003/0078255, and USPA 2003/0018023 for starting materials. 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, WO02/00651, WO02/102380, WO02/094197, USPA 2003/0078255, and USPA 2003/0018023 for starting materials. For compounds wherein G is a bicyclic moiety, one of ordinary skill in the art can look to WO98/57951 WO00/039108, WO00/39131, WO02/00651, WO02/102380, WO02/094197, USPA 2003/0078255, and USPA 2003/0018023 for starting materials. 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.
Compounds of the type where G is phenyl substituted with 0-2 R and 1-2 Ra and M is fused pyrazolo compound may be synthesized as shown in Scheme 22.




Additional compounds may be accessed where the pyrazole moiety is replaced by other heterocycles are described in WO 00/39131 and WO 03/26652.
Scheme 23 describes the synthesis of phenyl substituted pyrazoles. Additional examples may be found in WO 98/57951 and WO 99/32454.




Compounds of the type where G is phenyl substituted with 0-2 R and 1-2 Ra and M is phenyl may be synthesized as shown in Scheme 24 for carboxamides and Scheme 25 for sulfonamides.








One stereoisomer of a compound of Formula I may display superior activity compared with the other. Thus, compounds of the present invention may be chiral and accordingly in various enantiomeric forms. They therefore may exist in racemic or in optically active form. 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 described in Wilen, S. H. Tables of Resolving Agents and Optical Resolutions 1972, 308 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. An enantiomerically pure compound can be obtained with enantiomerically pure starting materials. Alternately, single stereoisomers can be obtained by chiral synthesis known to the person with skills in the art.
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 or cerebrovascular 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, atrial fibrillation, 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, arterial 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 Ki were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 min and the velocities (rate of absorbance change vs. time) were measured in the time frame of 25-30 min. The following relationship was used to calculate Ki values:

(vo−vs)/vs=I(Ki(1+S/Km))

    
    
        where:
        
            vo is the velocity of the control in the absence of inhibitor;
            vs is the velocity in the presence of inhibitor;
            I is the concentration of inhibitor;
            Ki is the dissociation constant of the enzyme:inhibitor complex;
            S is the concentration of substrate;
            Km is the Michaelis constant.
        
        
    
    


Compounds tested in the above assay are considered to be active if they exhibit a Ki of ≦10 μM. Preferred compounds of the present invention have Ki's of ≦1 μM. More preferred compounds of the present invention have Ki's of ≦0.1 μM. Even more preferred compounds of the present invention have Ki's of ≦0.01 μM. Still more preferred compounds of the present invention have Ki's of ≦0.001 μM. 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 40 min, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
The compounds of 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. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) 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 min 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 Ki of 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.
Additional therapeutic agents include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type), cardiac glycosides, diruetics, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal), anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti-anxiety agents, anti-proliferative agents, anti-tumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid receptor antagonist), anti-infective agents, anti-viral agents, anti-bacterial agents, and anti-fungal agents.
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, for example LOVENOXTM), synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and argatrobanas, factor VIIa, IXa, XIa inhibitors, 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, phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), 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 P2Y1 and P2Y12, with P2Y12 being even more preferred. Preferred P2Y12 receptor 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 (TPA, 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 IAch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in WO01/40231).
Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil); diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat, gemopatrilat and nitrates); and β-blockers (e.g., propanolol, nadolo, or carvedilol).
Examples of 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 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, fluvastatin, 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-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g., metformin); glucosidase inhibitors (e.g., acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g., repaglinide); sulfonylureas (e.g., glimepiride, glyburide and glipizide); biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.
Examples of suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.
Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2 inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and/or rofecoxib.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.
Examples of suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol.
Examples of suitable anti-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.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/min during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid-dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 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 The present invention 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 The present invention and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of The present invention and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
Where the compounds of The present invention are administered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of The present invention, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of The present invention.
Where two or more of the foregoing second therapeutic agents are administered with the compound of The present invention, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of The present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
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.
EXAMPLES
Example 1
2-[6-(2′-methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzamide




Part A: To a 0° C. solution of 5-methoxyanthranilic acid (5.0 g, 29.9 mmol) in concentrated hydrochloric acid (10 mL) was added dropwise an ice cold solution of sodium nitrite (2.06 g, 29.9 mmol) in water (5 mL) and stirring was continued at 0° C. for 30 minutes. Stannous chloride dihydrate (16.8 g, 74.8 mmol) was dissolved in concentrated hydrochloric acid (16 mL), cooled to 0° C., and added slowly to the solution of the diazonium salt. The precipitate was agitated, kept at 0° C. for 30 minutes, and then filtered. The solids were washed successively with ice cold brine and petroleum ether and dried under a stream of air and then under vacuum. The crude hydrazine salt and 3-hydroxy-1-(4-iodo-phenyl)-4-(2,2,2-trifluoro-acetyl)-5,6-dihydro-1H-pyridin-2-one (12.3 g, 29.9 mmol) were combined in glacial acetic acid (50 mL) and heated to 80° C. Upon completion of the reaction the solvent was evaporated to a viscous oil which was subjected to silica gel column chromatography to yield 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester (4.12 g, 24%). MS (AP+) 571.9 (100%).
Part B: 2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester (2.00 g, 3.50 mmol), 2-(methylthio)phenylboronic acid (647 mg, 3.85 mmol), bis(triphenylphosphine)palladium(II) chloride (122 mg, 0.175 mmol), tetrabutylammonium bromide (56 mg, 0.175 mmol), and sodium carbonate (1.11 g, 10.5 mmol) were combined, the flask purged with argon and degassed benzene (50 mL) and water (5 mL) were added. The flask was heated to reflux for 14 h, cooled to ambient temperature, and poured into ethyl acetate/water. The phases were separated and the aqueous phase extracted once with ethyl acetate. The organic phases were combined, dried over sodium sulfate, filtered, and evaporated. The crude 5-methoxy-2-[6-(2′-methylsulfanyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-benzoic acid methyl ester was dissolved in dichloromethane (50 mL) and meta-chloroperbenzoic acid (2.41 g, 70%, 9.8 mmol) was added as a solid. Upon completion the reaction was poured into water (50 mL), and sodium sulfite was added until the aqueous layer tested negative to starch/potassium iodide paper. The phases were separated, and the organic was washed once with sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated. The solid was subjected to silica gel column chromatography to yield 2-[6-(2′-methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester (1.70 g, 81%) as a colorless solid. This material (1.69 g, 2.81 mmol) was stirred in dioxane (15 mL) and 10% sodium hydroxide (15 mL). The reaction was acidified with concentrated hydrochloric acid to pH 3 and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (5×10 mL), dried over sodium sulfate, filtered, and evaporated. 2-[6-(2′-Methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid was isolated as a colorless solid in nearly quantitative yield. This material (59.2 mg, 0.101 mmol) was dissolved in dry chloroform (3 mL) to which was added thionyl chloride (37 μL, 0.505 mmol), and the reaction heated to reflux. The solvent was evaporated, and the residue dried under vacuum to give 2-[6-(2′-methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin 1-yl]-5-methoxy-benzoyl chloride.
Part C: 2-[6-(2′-Methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride (0.10 mmol) was dissolved in dry dichloromethane (1 mL) under a nitrogen atmosphere, and a stream of ammonia gas was introduced for 30 sec. The solvent was evaporated, and the residue was purified by reverse phase HPLC to give the title compound as a colorless solid. MS (ES+) 607.1 (M+Na)+(100%); 1H NMR (DMSO-d6) δ 8.08 (d, 1H, J=6.6 Hz), 7.79-7.34 (m, 10H), 7.16 (d, 1H, J=2.9 Hz), 7.09 (dd, 1H, J=8.5, 2.6), 4.11 (t, 2H, J=6.4 Hz), 3.84 (s, 3H), 3.11 (t, 2H, J=6.4), 2.81 (s, 3H).
Example 2
2-[6-(2′-Methanesulfonyl-biphenyl-4-yl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-benzamide




The title compound was synthesized from 2-aminobenzoic acid methyl ester in an analogous manner to Example 1. MS (ES+) 555.1 (M+H)+(100%).
Examples 3-32
The compounds shown in Table 1 (examples 3-32) were prepared in an analogous manner to Example 1 employing the general procedure (Example 1, part C) and substituting the appropriate amine.










TABLE 1





Ex.
Structure
MF
MS:(M + H)+


















3




C32H32F3N5O5S
656.2


 


4




C33H29F3N6O5S
679.2


 


5




C33H26F3N5O5S
662.2


 


6




C34H28F3N5O5S
676.2


 


7




C36H32F3N5O5S
704.2


 


8




C30H28F3N5O5S
628.2


 


9




C31H30F3N5O5S
642.2


 


10




C35H36F3N5O5S
696.2


 


11




C33H32F3N5O5S
668.2


 


12




C31H29F3N4O6S
643.2


 


13




C33H26F3N5O5S
662.2


 


14




C33H32F3N5O5S
668.2


 


15




C33H34F3N5O5S
670.2


 


16




C34H33F3N4O6S
683.2


 


17




C32H29F3N4O6S
655.2


 


18




C36H31F3N4O6S
705.2


 


19




C36H31F3N4O6S
705.2


 


20




C32H31F3N4O7S
673.2


 


21




C31H29F3N4O6S
643.2


 


22




C31H29F3N4O6S
643.2


 


23




C33H31F3N4O6S
669.2


 


24




C36H31F3N4O6S
705.2


 


25




C31H29F3N4O7S
659.2


 


26




C30H27F3N4O6S
629.2


 


27




C31H29F3N4O6S
643.2


 


28




C33H31F3N4O6S
669.2


 


29




C37H31F3N4O6S
717.2


 


30




C34H27F3N4O6S
677.2


 


31




C30H27F3N4O6S
629.2


 


32




C32H27F3N6O5S
665.2









Example 33
5-Methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-2-{7-oxo-6-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamide, trifluoroacetic acid salt




The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (159 mg, 0.278 mmol) was dissolved in ethylene glycol (2 mL) containing 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (400 μL, 2.78 mmol) and heated to 85° C. for 12 h. The reaction was poured into water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (5×10 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative thin layer chromatography to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (60 mg, 32%) as a faint yellow solid. MS (ES+) 668.4 (M+H)+(100%). This material (60 mg, 0.089 mmol) was combined with 2-pyridone (17 mg, 0.18 mmol), anhydrous potassium carbonate (49 mg, 0.36 mmol), copper(I) iodide (3.4 mg, 0.018 mmol), 1,10-phenanthroline (3.2 mg, 0.018 mmol), and dry-degassed dimethylsulfoxide (1.0 mL) and heated to 140° C. for 6 h. The mixture was cooled to ambient temperature and diluted with 6N ammonium hydroxide and ethyl acetate. The phases were separated, and the aqueous phase extracted once with ethyl acetate. The combined organic extracts were washed successively with water (2×) and 3N ammonium hydroxide, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 635.5 (M+H)+(100%).
Example 34
2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-pyridin-3-yl-benzamide




The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (270 mg, 0.47 mmol) was stirred in tetrahydrofuran (1 mL) and 10% sodium hydroxide (1 mL) for 5 h. The reaction was acidified with 1N hydrochloric acid to pH 3 and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (2×5 mL), dried over sodium sulfate, filtered, and evaporated to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid (263 mg, 100%) as a colorless solid. The acid (263 mg, 0.47 mmol) was dissolved in dimethylformamide (3 mL) to which were added triethylamine (233 mL, 1.68 mmol) and 3-aminopyridine (54 mg, 0.58 mmol). After 10 minutes benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) was added and stirring continued for 24 hr. The reaction was poured into ethyl acetate/water, and the phases were separated. The aqueous was extracted twice with ethyl acetate. The combined organics were washed with water (4×) and once with brine, dried over sodium sulfate, filtered, and evaporated to give 278 mg (91%) of a light orange colored solid. The material was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 634.0 (M+H)+(100%).
Example 35
5-Methoxy-2-(7-oxo-6-phenyl-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-N-pyridin-3-yl-benzamide




2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-pyridin-3-yl-benzamide (15 mg, 0.023 mmol) was combined with 5% palladium on carbon and stirred in ethanol under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered through diatomaceous earth and the solvent evaporated to give the title compound (11 mg, 95%) as a colorless solid. MS (ES+) 508.0 (M+H)+(100%).
Example 36
N-(1H-Imidazol-2-ylmethyl)-2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzamide, bis-trifluoroacetic acid salt




2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid (186 mg, 0.334 mmol) was dissolved in dry chloroform (10 mL) to which was added thionyl chloride (243 μL, 3.34 mmol), and the reaction heated to reflux. The solvent was evaporated, and the residue dried under vacuum to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride as a pale yellow foam. This material was dissolved in dry methylene chloride (10 mL) to which were added pyridine (0.14 mL, 1.67 mmol), N,N-dimethylaminopyridine (4 mg, 0.033 mmol), and lastly C-(1H-imidazol-2-yl)-methylamine bis-hydrochloride (114 mg, 0.668 mmol). Upon completion of the reaction the solvent was evaporated, and the residue was purified by preparative HPLC to give the title compound (69 mg, 24%) as a colorless solid. MS (ES+) 636.9 (M+H)+(100%).
Examples 37-45
The compounds shown in Table 2 (examples 37-45) were prepared in an analogous manner to Example 1 employing the general procedure (Example 1, part C) and substituting the appropriate amine.










TABLE 2





Ex.
Structure
MF
(M + H)+







37




C26H31N5O6S
542.2


 


38




C25H29N5O6S
528.2


 


39




C28H28N6O5S
561.2


 


40




C28H28N6O5S
561.2


 


41




C28H28N6O5S
561.2


 


42




C26H31N5O6S
542.2


 


43




C26H31N5O6S
542.2


 


44




C27H29N7O5S
564.2


 


45




C23H25N5O5S
484.2









Example 46
2-[6-(4-Chloro-phenyl)-3-methyl-7-oxo-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzenesulfonamide




(2-[6-(4-Chloro-phenyl)-3-methyl-7-oxo-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzenesulfonic acid is synthesized from anisidine-2-sulfonic acid in an analogous manner as described in Example 1.
Examples 47-61
The compounds shown in Table 3 (examples 47-61) were prepared in analogous manner to Example 46 employing the general procedure (example 1) and methods described in WO 03/26652 and substituting the appropriate amine.










TABLE 3





Ex.
Structure
MF
(M + H)+







47




C27H23F3N4O6
621.1


 


48




C27H23F3N4O4S2
589.1


 


49




C26H26F3N7O4S
590.2


 


50




C24H21F3N6O4S
547.1


 


51




C24H18F3N5O4S
530.1


 


52




C25H24F3N7O3S
560.2


 


53




C27H24F3N5O3S
556.2


 


54




C28H26F3N5O3S
570.2


 


55




C30H28F3N5O4S
612.2


 


56




C31H30F3N5O4S
626.2


 


57




C26H21F3N4O3S2
559.1


 


58




C19H14F3IN4O3S
563.0


 


59




C26H21F3N4O5S2
591.1


 


60




C24H22F3N5O4S
534.1


 


61




C26H20F3N5O5S
572.1









Examples 62-106
The compounds shown in Table 4 (examples 62-106) were prepared according to the general procedure described below.




Part A: Preparation of 2-(5-furan-2-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methoxy-benzoic acid methyl ester. To a solution of 2-amino-5-methoxy-benzoic acid methyl ester hydrochloride (201 mg, 0.922 mmol) in 1N hydrochloric acid (6 mL) cooled to 0° C. was added dropwise an ice cold solution of sodium nitrite (68 mg, 0.992 mmol) in water (1 mL). The solution was stirred at 0° C. for 45 minutes after which an ice cold solution of stannous chloride dihydrate (520 mg, 2.30 mmol) in 1N hydrochloric acid (2 mL) was added dropwise and stirred rapidly for an additional 15 min. at 0° C. A solution of 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione in methanol (2 mL) was added, the cooling bath removed, and the reaction allowed to warm to ambient temperature. The solution was heated to 50° C. for 15 h and upon completion of the reaction the solvent volume was reduced under reduced pressure. Ethyl acetate was added, and the phases were separated. The aqueous layer was extracted once with ethyl acetate, and the combined organics were washed once with water, brine, dried over sodium sulfate, filtered, and evaporated to give 270 mg (80%) of 2-(5-furan-2-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methoxy-benzoic acid methyl ester.
Part B: Preparation of 2-(4-methoxy-2-methoxycarbonyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid. A solution 2-(5-furan-2-yl-3-trifluoromethyl-pyrazol-1-yl)-5-methoxy-benzoic acid methyl ester (1.00 g, 2.73 mmol) in acetonitrile (9 mL) was added to a solution of sodium dihydrogenphosphate (1.63 g, 13.6 mmol) in water (2 mL) cooled to 0° C. To this mixture was added, using an addition funnel, a solution of sodium chlorite (3.1 g, 80%, 27.3 mmol) in water (9 mL) in three equal portions with ten minutes between each addition. The reaction was allowed to warm to ambient temperature and stirred for 14 h. Upon completion of the reaction, a solution of 1N sodium hydroxide (10 mL) was added, and the mixture was extracted with chloroform (2×25 mL). The combined chloroform extracts were extracted with saturated sodium bicarbonate. The combined basic layers were made acidic (pH 2.0) with concentrated hydrochloric acid and extracted twice with ethyl acetate, dried over magnesium sulfate, and evaporated to give 348 mg (37%) of 2-(4-methoxy-2-methoxycarbonyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid.
Part C: Preparation of 2-[5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxy-benzoic acid methyl ester. 3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylamine (231 mg, 0.87 mmol) and 2-(4-methoxy-2-methoxycarbonyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (300 mg, 0.87 mmol) were combined in a flask and placed under a nitrogen atmosphere. Pyridine (4.0 mL) was added, and the flask was cooled to −15° C. After stirring for five minutes, phosphorous oxychloride (97 μL, 1.04 mmol) was added dropwise followed by additional stirring for one hour while maintaining a reaction temperature of −10 to −15° C. The reaction was diluted with dichloromethane, washed with 0.1 M hydrochloric acid (3×), dried over magnesium sulfate, filtered, evaporated under reduced pressure, and dried under high vacuum for 12 h. 2-[5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxy-benzoic acid methyl ester (514 mg, 84%) was isolated in sufficient purity to be used in the next step.
Part D: Preparation of 2-[5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxy-benzoic acid. 2-[5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxybenzoic acid methyl ester (1.70 g, 2.80 mmol) was dissolved in methanol (22 mL), 1N sodium hydroxide (5.8 mL) was added, and the solution refluxed for 6 hours. The reaction was cooled to ambient temperature and diluted with water (30 mL). 3N hydrochloric acid was added to adjust the pH to 2, and the resulting precipitate collected by filtration. The solid was dried under vacuum in a desiccator to give 1.45 g (86%) of (3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxy-benzoic acid. 1H NMR (CD3OD) δ 8.12 (dd, J=1.5, 8.1 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.70 (dt, J=1.5, 7.7 Hz, 1H), 7.61 (dt, J=1.5, 7.7 Hz, 1H), 7.37 (m, 3H), 7.25 (dd, J=2.2, 11.7 Hz, 1H) 7.16 (m, 3H) 3.87 (s, 3H), 2.67 (s, 3H).




Part E: Preparation of tert-Butoxycarbonylamino-N-alkylcarboxamides: tert-Butoxycarbonylamino-carboxylic acid (0.50 mmol) was dissolved in N,N-dimethylformamide (6.0 mL); 1-hydroxybenzotriazole (132 mg, 0.98 mmol) was added and the solution was stirred at ambient temperature for 30 minutes. 1,3-Diisopropylcarbodiimide (153 mg, 0.98 mmol) and amine (0.50 mmol) were added and stirring continued for 12 h at ambient temperature. PS-Trisamine (592 mg, 2.0 mmol) was added and stirring continued for three hours, after which the reaction was filtered and the solvent evaporated. To the residue was added trifluoroacetic acid/dichloromethane (1:1)(1.5 mL), stirring was continued for 30 minutes, and the solvent was evaporated under reduced pressure, yielding a nearly quantitative yield (crude) of a yellow-orange amorphous solid.
To a portion of the carboxylic acid 3 (0.134 mmol) was added dimethylformamide (1.0 mL) followed by 1-hydroxybenzotriazole (21 mg, 0.134 mmol) and 1,3-diisopropylcarbodiimide (17 mg, 0.134 mmol), which was then stirred for 30 minutes at ambient temperature. 2-[5-3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxybenzoic acid (20 mg, 0.067 mmol) and N,N-diisopropylethylamine (35 μL, 0.201 mmol) were added and stirring was continued at ambient temperature for 12 h. The solvent was evaporated under reduced pressure and the residue purified by reverse phase HPLC, collecting products using a mass-directed trigger.










TABLE 4








MS:(M +


Ex.
Structure
MF
H)+


















62




C36H31F4N5O6S
738.2


 


63




C37H33F4N5O6S
752.2


 


64




C36H30ClF4N5O6S
772.2


 


65




C37H32ClF4N5O6S
786.2


 


66




C36H30ClF4N5O6S
772.2


 


67




C36H29F4N5O8S
768.2


 


68




C38H33F4N5O8S
796.2


 


69




C37H31F4N5O8S
782.2


 


70




C39H36F4N6O8S
825.2


 


71




C37H31F4N5O9S
798.2


 


72




C43H35F4N5O8S
858.2


 


73




C34H34F4N6O7S
747.2


 


74




C35H36F4N6O7S
761.2


 


75




C36H38F4N6O7S
775.3


 


76




C35H29F4N5O6S
724.2


 


77




C38H36F4N6O6S
781.2


 


78




C42H35F4N5O6S
814.2


 


79




C35H28ClF4N5O6S
758.1


 


80




C37H30ClF4N5O8S
816.2


 


81




C38H35ClF4N6O6S
815.2


 


82




C36H30ClF4N5O7S
788.2


 


83




C42H34ClF4N5O6S
848.2


 


84




C38H35F4N5O7S
782.2


 


85




C32H30F4N6O7S
719.2


 


86




C33H32F4N6O7S
733.2


 


87




C34H34F4N6O7S
747.2


 


88




C31H29F4N5O7S
692.2


 


89




C32H31F4N5O7S
706.2


 


90




C33H33F4N5O7S
720.2


 


91




C36H31F4N5O6S
738.2


 


92




C37H33F4N5O6S
752.2


 


93




C38H35F4N5O6S
766.2


 


94




C39H38F4N6O6S
795.3


 


95




C37H33F4N5O7S
768.2


 


96




C43H37F4N5O6S
828.2


 


97




C31H29F4N5O6S
676.2


 


98




C32H31F4N5O6S
690.2


 


99




C32H31F4N5O6S
690.2


 


100




C33H31F4N5O8S
734.2


 


101




C34H36F4N6O6S
733.2


 


102




C32H31F4N5O7S
706.2


 


103




C26H20F4N4O5S
577.1


 


104




C33H26F4N4O5S
667.2


 


105




C45H48F4N6O9S
925.3


 


106




C42H43F4N5O9S
870.3









Example 107
2-(2-Carbamoyl-4-methoxy-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (4-dimethylamino-phenyl)-amide




The title compound was prepared in a analogous manner to the general procedure for examples 62-106. C21H20F3N5O3. MS:(M+H)+ 448.2.
Examples 108-255







Part A: Preparation of 3-chloro-5,6-dihydro-1H-pyridin-2-one. A solution of piperidin-2-one (900 g, 9.08 mol) in chloroform (2 L) was added to a stirred mixture of phosphorous pentachloride (5.66 kg, 27.2 mol) in chloroform (10 L). Additional chloroform (6 L) was added, and the mixture heated under reflux for 21 h. The cooled mixture was added to ice while keeping the temperature around 10° C. The pH was adjusted to 9-10 by adding 50% aqueous sodium hydroxide while keeping the temperature below 40° C. The phases were separated and the aqueous phase extracted with dichloromethane (5 L). The combined organic phases were washed with brine (5 L), dried, and concentrated under vacuum to give 1-benzyl-3,3-dichloro-piperidin-2-one (1200 g, 79%), which was used for the following step without further purification.
Part B: Preparation of 3-chloro-5,6-dihydro-1H-pyridin-2-one. Lithium chloride (290 g, 6.84 mol) and lithium carbonate (505 g, 6.84 mol) were added to a stirred mixture of 1-benzyl-3,3-dichloro-piperidin-2-one (1150 g, 6.84 mol) in dimethylformamide (4.8 L) and the mixture heated at 130° C. for 4.5 h. The reaction mixture was cooled to 70° C. and then concentrated in vacuo to remove approximately 3 L of dimethylformamide. The mixture was cooled to 45-50° C. and ethyl acetate (4.5 L) was added. The mixture was cooled to 0-5° C. overnight. The resulting mixture was filtered through diatomaceous earth, washing the filter bed with ethyl acetate (4.5 L). The filtrate was concentrated under vacuum, and the residue was purified by chromatography (9:1 dichloromethane/methanol) followed by trituration with hexanes/toluene (3:1) to give 3-chloro-5,6-dihydro-1H-pyridin-2-one (620 g, 70%).
Part C: Preparation of 1-benzyl-3-chloro-5,6-dihydro-1H-pyridin-2-one. A mixture of 3-chloro-5,6-dihydro-1H-pyridin-2-one (40 g, 304 mmol) and benzyl bromide (104 g, 608 mmol) in tetrahydrofuran (800 mL) was added to a suspension of potassium hydride (18.3 g, 456 mmol) in tetrahydrofuran (800 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 20 h, then quenched cautiously with water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried, and concentrated under vacuum. The residue was purified by column chromatography (9:1 to 1:1 hexanes/ethyl acetate) to give 1-benzyl-3-chloro-5,6-dihydro-1H-pyridin-2-one (41 g, 61%).
Part D: Preparation of 1-benzyl-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one. A mixture of 1-benzyl-3-chloro-5,6-dihydro-1H-pyridin-2-one (41 g, 185 mmol) and morpholine (500 mL) was heated under reflux for 24 h and then concentrated under vacuum. The residue was purified by column chromatography (7:3 to 1:1 hexanes/ethyl acetate) to give 1-benzyl-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (35.4 g, 70%).
Part E. Preparation of 1-benzyl-3-morpholin-4-yl-4-(2,2,2-trifluoro-acetyl)-5,6-dihydro-1H-pyridin-2-one. Trifluoroacetic anhydride (32.8 g, 156 mmol) was added to a solution of 1-benzyl-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (35.4 g, 130 mmol) and N,N-dimethyaminopyridine (19.1 g, 156 mmol) in dichloromethane (875 mL) at OC, while maintaining the internal temperature below 5° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h and then quenched with water and extracted with dichloromethane. The combined organic phases were washed with water and then brine, dried, and concentrated under vacuum to give 1-benzyl-3-morpholin-4-yl-4-(2,2,2-trifluoro-acetyl)-5,6-dihydro-1H-pyridin-2-one (44.3 g, 92%), which was used in the following step without further purification.
Part F: Preparation of 1-benzyl-4-(2,2,2-trifluoro-acetyl)-piperidine-2,3-dione. A mixture of 1-benzyl-3-morpholin-4-yl-4-(2,2,2-trifluoro-acetyl)-5,6-dihydro-1H-pyridin-2-one (44.3 g, 120 mmol), diethyl ether (1300 mL), and 6 M hydrochloric acid (1300 mL) was stirred at room temperature for 16 h and then extracted with tert-butyl methyl ether. The combined extracts were washed with water and then with brine, dried, and concentrated under vacuum to give 1-benzyl-4-(2,2,2-trifluoro-acetyl)-piperidine-2,3-dione (31.8 g, 89%), which was used in the following step without further purification.
Part G: Preparation of 2-(6-benzyl-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-5-methoxy-benzoic acid methyl ester. A mixture of 1-benzyl-4-(2,2,2-trifluoro-acetyl)-piperidine-2,3-dione (13.2 g, 44.1 mmol) and 2-hydrazino-5-methoxy-benzoic acid methyl ester hydrochloride (14.4 g, 61.7 mmol) in acetic acid (400 mL) was heated under reflux for 22 h and then concentrated under vacuum. The residue was purified by column chromatography (2:1 hexanes/ethyl acetate) to give 2-(6-benzyl-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-5-methoxy-benzoic acid methyl ester (15 g, 74%).
Part H: Preparation of 5-Methoxy-2-(7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-benzoic acid methyl ester. A mixture of 2-(6-benzyl-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-5-methoxy-benzoic acid methyl ester (22 g, 47.9 mmol), 20% Pd(OH)2/C (9.8 g), methanol (120 mL), and 4M hydrochloric acid in dioxane (50 mL) was hydrogenated at 50 psi hydrogen at 50° C. for 90 h. The mixture was cautiously filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (7:3 hexanes/ethyl acetate) to give 5-methoxy-2-(7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-benzoic acid methyl ester (11 g, 62%).




Part I: Preparation of 5-methoxy-2-(7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-benzoic acid bis-potassium salt. Potassium hydroxide pellets (118 mg, 2.1 mmol) were dissolved in methanol (5 mL) with stirring. 5-Methoxy-2-(7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-benzoic acid methyl ester (370 mg, 1.0 mmol) was added in one portion with stirring. The solid did not completely dissolve before microwave heating at 120° C. for 15 minutes. The solution was evaporated under a nitrogen stream to give a colorless residue. LC/MS M−H=354.4.
Part J: Preparation of 2-[6-(4-dimethylcarbamoyl-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid. 4-Iodo-N,N-dimethylbenzamide (410 mg, 1.5 mmol) and tetrakisacetonitrilecopper(I) hexafluorophosphate (37.2 mg, 0.1 mmol) were dissolved in degassed dimethylsulfoxide (5 mL) and added to 5-methoxy-2-(7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl)-benzoic acid bis-potassium salt. This mixture was vigorously stirred to dissolve the solids. The solution was purged with nitrogen before heating in a microwave at 150° C. for 60 minutes. After cooling to ambient temperature the resulting brown solution was quickly added to aqueous 1N hydrochloric acid (100 ml) to produce a yellow suspension which was stirred for 30 minutes. The yellow solid was collected by filtration and washed with water (30 mL), dissolved in ethyl acetate (50 mL) and extracted into aqueous sodium bicarbonate (20 mL water and 3 mL saturated sodium bicarbonate). The ethyl acetate was extracted a second time with aqueous sodium bicarbonate and the aqueous extracts combined and washed with ethyl acetate (50 mL). The aqueous extract was acidified with aqueous 1N hydrochloric acid (15 mL) and extracted twice with ethyl acetate (30 mL). The combined ethyl acetate extracts were washed with water (20 mL), dried over sodium sulfate, filtered, and evaporated to give 410 mg (80%) of 2-[6-(4-dimethylcarbamoyl-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxybenzoic acid as an amber glass in 85% purity. LC/MS (M+H)+: 503.3. 1H NMR (CD3OD) δ 7.53 (d, J=2.9 1H), 7.40 (m, 5H), 7.2 (dd, J=2.9, 8.8 Hz, 1H), 4.10 (t, J=6.6 Hz, 2H), 3.85 (s, 3H), 3.15 (t, J=6.6 Hz, 2H), 3.05 (s, 3H), 2.95 (s, 3H).
Preparation of 2-[6-(4-dimethylcarbamoyl-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxybenzamides: 2-[6-(4-dimethylcarbamoyl-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxybenzoic acid (10 mg, 0.020 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (5.8 mg, 0.030 mmol), 1-hydroxybenzotriazole (4.6 mg, 0.030 mmol), and N,N-diisopropylethyl amine (18 mL, 0.100 mmol) were combined in dichloromethane (0.350 mL). After 15 minutes, this solution was added to a mixture of the amine and n-methylpyrrolidinone (0.050 mL) and shaken at ambient temperature for 12 h. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC, collecting products using a MS trigger.










TABLE 5





Ex.
Structure
MF
(M + H)+







108




C24H22F3N5O4
502.2


 


109




C33H31F3N6O5
649.2


 


110




C31H35F3N6O6
645.3


 


111




C37H38F3N7O7
750.3


 


112




C32H38F3N7O5
658.3


 


113




C34H32ClF3N6O5
697.2


 


114




C35H35F3N6O6
693.3


 


115




C34H31F3N6O7
693.2


 


116




C29H31F3N6O5
601.2


 


117




C34H31F3N6O7
693.2


 


118




C34H31F3N6O7
693.2


 


119




C28H30F3N5O5
574.2


 


120




C33H32F3N5O4
620.2


 


121




C31H26F3N5O6
622.2


 


122




C26H26F3N5O4
530.2


 


123




C32H30F3N5O5
622.2


 


124




C31H27ClF3N5O4
626.2


 


125




C31H26F3N5O6
622.2


 


126




C31H26F3N5O6
622.2


 


127




C24H22F3N5O4
502.2


 


128




C21H17F3N4O3
431.1


 


129




C22H19F3N4O3
445.1


 


130




C23H21F3N4O3
459.2


 


131




C24H23F3N4O3
473.2


 


132




C25H25F3N4O3
487.2


 


133




C22H19F3N4O4
461.1


 


134




C20H16F3N5O3
432.1


 


135




C27H26F3N5O4
542.2


 


136




C29H30F3N5O4
570.2


 


137




C31H35F3N6O4
613.3


 


138




C29H26F3N5O5
582.2


 


139




C29H26F3N5O4S
598.2


 


140




C32H28F3N5O6
636.2


 


141




C30H33F3N6O5
615.3


 


142




C30H27F3N6O4
593.2


 


143




C31H29F3N6O4
607.2


 


144




C30H27F3N6O4
593.2


 


145




C30H27F3N6O4
593.2


 


146




C36H37F3N6O4
675.3


 


147




C30H26F3N5O4
578.2


 


148




C31H28F3N5O5
608.2


 


149




C31H28F3N5O5
608.2


 


150




C30H25ClF3N5O4
612.2


 


151




C31H28F3N5O5
608.2


 


152




C32H30F3N5O4
606.2


 


153




C31H28F3N5O4
592.2


 


154




C31H27F4N5O4
610.2


 


155




C31H27ClF3N5O4
626.2


 


156




C32H30F3N5O5
622.2


 


157




C33H32F3N5O5
636.2


 


168




C28H29F3N6O5
587.2


 


169




C28H31F3N6O4
573.2


 


170




C27H28F3N5O5
560.2


 


171




C27H28F3N5O4
544.2


 


172




C29H32F3N5O5
588.2


 


173




C30H30F3N7O4
610.2


 


174




C28H28F3N5O4
556.2


 


175




C32H28F3N5O5
620.2


 


176




C29H33F3N6O4
587.3


 


177




C32H29ClF3N5O4
640.2


 


178




C31H27ClF3N5O4
626.2


 


179




C32H29F4N5O4
624.2


 


180




C33H32F3N5O5
636.2


 


181




C32H29ClF3N5O4
640.2


 


182




C32H27F6N5O5
676.2


 


183




C32H27F6N5O5
676.2


 


184




C33H32F3N5O4
620.2


 


185




C32H27F6N5O5
676.2


 


186




C33H32F3N5O4
620.2


 


187




C31H33F3N6O4
611.3


 


188




C30H28F3N5O5
596.2


 


189




C33H32F3N5O4
620.2


 


190




C33H30F3N5O4
618.2


 


191




C33H32F3N5O5
636.2


 


192




C29H25F3N6O4
579.2


 


193




C32H30F3N5O4
606.2


 


194




C33H32F3N5O4
620.2


 


195




C33H32F3N5O5
636.2


 


196




C31H34F3N5O4
598.3


 


197




C28H27F3N6O4
569.2


 


198




C32H36F3N5O4
612.3


 


199




C27H26F3N5O4
542.2


 


200




C27H26F3N5O4
542.2


 


201




C27H26F3N5O4S
574.2


 


202




C28H26F3N5O4
554.2


 


203




C28H28F3N5O4
556.2


 


204




C29H29F3N6O5
599.2


 


205




C30H32F3N5O4
584.2


 


206




C29H28F3N5O4
568.2


 


207




C34H33F3N6O4
647.3


 


208




C34H32F4N6O4
665.2


 


209




C29H29F3N6O4
599.2


 


210




C29H31F3N6O4
585.2


 


211




C35H35F3N6O4
661.3


 


212




C34H38F3N7O5
682.3


 


213




C33H38F3N7O5
670.3


 


214




C28H28F3N5O5
572.2


 


215




C30H32F3N5O5
600.2


 


216




C28H28F3N5O4S
588.2


 


217




C31H32F3N5O6
628.2


 


218




C29H30F3N5O4
570.2


 


219




C30H32F3N5O4
584.2


 


220




C31H34F3N5O4
598.3


 


221




C31H34F3N5O4
598.3


 


222




C34H39F3N6O5
669.3


 


223




C30H31F3N6O5
613.2


 


224




C30H32F3N5O4
584.2


 


225




C31H34F3N5O4
598.3


 


226




C31H34F3N5O4
598.3


 


227




C35H34F3N5O4
646.3


 


228




C30H32F3N5O4
584.2


 


229




C33H32F3N7O4
648.3


 


230




C34H33F3N6O4
647.3


 


231




C34H39F3N6O4
653.3


 


232




C31H35F3N6O4
613.3


 


233




C33H30F3N5O4
618.2


 


234




C26H26F3N5O4
530.2


 


235




C28H26F3N5O4
554.2


 


236




C30H35F3N6O4
601.3


 


237




C31H37F3N6O4
615.3


 


238




C28H30F3N5O4
558.2


 


239




C30H34F3N5O4
586.3


 


240




C30H32F3N5O5
600.2


 


241




C33H37F3N6O4
639.3


 


242




C29H32F3N5O4
572.2


 


243




C29H32F3N5O4
572.2


 


244




C35H35F3N6O4
661.3


 


245




C35H35F3N6O4
661.3


 


246




C32H37F3N6O4
627.3


 


247




C32H31F3N6O4
621.2


 


248




C30H34F3N5O6
618.3


 


249




C33H37F3N6O4
639.3


 


250




C30H31F3N6O5
613.2


 


251




C33H31F3N6O6
665.2


 


252




C32H36F3N5O4
612.3


 


253




C35H41F3N6O4
667.3


 


254




C37H39F3N6O4
689.3


 


255




C37H39F3N6O4
689.3









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

## Claims

1. A compound selected from the group:







































































































or a pharmaceutically acceptable salt form thereof.

2. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

3. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof.

4. A method according to claim 3, 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.

5. A method according to claim 3, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (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.