# Patent

## Title
Monocyclic and bicyclic lactams as factor Xa inhibitors

## Abstract

The present application describes monocyclic and bicyclic lactams and derivatives thereof of Formulae Ia–e:




wherein one of one of T1 and T2 is carbonyl, thiocarbonyl, or sulfonyl 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. 60/507,533, filed Oct. 1, 2003, which is expressly incorporated fully herein by reference.


FIELD OF THE INVENTION
This invention relates generally to monocyclic and bicyclic lactams 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 monocyclic and bicyclic lactams and derivatives thereof that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method for treating thromboembolic disorders comprising administering to a 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 or prodrug form thereof.
The present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
The present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
The present invention provides novel 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 monocyclic and bicyclic lactams of Formulae Ia–e:




wherein one of one of T1 and T2 is carbonyl, thiocarbonyl, or sulfonyl and G, G1, A, B, R1a, Z1, and Z2 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 Ia, Ib, Ic, Id, or Ie:




or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

the central lactam ring of Ia, Ib, and Ic is substituted with 0–2 R1a;
one of T1 and T2 is selected from C(O), C(S), and S(O)2 and the other is selected from C(O), C(S), S(O)2, CH2, and CHOH;
one of Z1 and Z2 is N and the other is C;
G is a group of formula IIa or IIb:




ring D, including the two atoms of Ring E to which it is attached, is a 5–6 membered ring consisting of carbon atoms and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)p;
ring D is substituted with 0–2 R and there are 0–3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1–3 R;
alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1–3 R;
alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5–6 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5–6 membered heterocycle is substituted with 0–2 carbonyls and 1–3 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, 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, C(═NR8)NR7R9, NHC(═NR8)NR7R9, ONHC(═NR8)NR7R9, NR8CH(═NR7), (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, provided that S(O)pR7 and S(O)2R3 form other than S(O)2H or S(O)H;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
G1 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)uNRR3e(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)uNR3bC(O)(CR3R3a)uC(S)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(S)(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;
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 lactam nitrogen 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;
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—;
Y is selected from: CY1Y2R4a, NR3R3a, C(O)NR3R3a, SO2R3, SO2NR3R3a, 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;
when ring A has 0–1 ring double bonds, then Y is additionally selected from C1-6 alkyl, C1-4 haloalkyl, —CN, C(O)R3, C(O)OR3, S(O)pR3, S(O)2NR3R3, OR3, NR3C(O)R3, C(O)NR3SO2R3, NR3C(O)NR3R3, NR3R3, C(S)R3, NR3C(S)NR3R3, C(S)OR3, and NR3C(O)R3;
Y1 and Y2 are independently C1-4 alkyl substituted with 0–2 R4;
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)4-5–10 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)4-5–10 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)4-5–10 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)4-5–10 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)4-5–10 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)4-5–10 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 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 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 0-2R1a, —(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)4-5–6 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)4-5–6 membered carbocycle substituted with 0–1 R5, and a (CR3R3a)4-5–6 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)4-5–10 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)r-4–10 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)4-5–6 membered carbocycle substituted with 0–1 R5, and a (CR3R3a)4-5–6 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 selected from formula Ia, Ib, and Ic, wherein:
G is a group of formula IIa or IIb:




ring D, including the two atoms of ring E to which it is attached, is a 5–6 membered ring consisting of: carbon atoms and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)p;
ring D is substituted with 0–2 R and there are 0–3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1–2 R;
alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1–2 R;
alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with a 5 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5 membered heterocycle is substituted with 0–1 carbonyls and 1–2 R and has 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, 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, and OCF3;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
G1 is selected from (CR3R3a)2-4, (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)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, (CR3R3a)uS(O)2NR3b(CR3R3a)w, and (CR3R3a)uNR3e(CR3R3a)w, wherein u+w total 1, 2, or 3 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;
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 the lactam nitrogen 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—CR4═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, SO2NR3R3a, 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, tetrahydropyranyl, 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;
alternatively, when A is selected from one of the following carbocyclic and heterocyclic groups, which are substituted with 0–2 R4c,cyclohexyl, cyclopentyl, azetidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, morpholinyl, and pyrrolidinyl;
then Y is additionally selected from methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 1,1-dimethyl-1-ethyl, 1-pentyl, 2-pentyl, 3-pentyl, 3-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, 2,5-dimethyl-cyclopentyl, cyclohexyl, 2,6-dimethyl-cyclohexyl, CH(CF3)2, CH(CHF2), CH(CH2F), CH2CF3, CH(CF2CF3)2, CH(Cl)CF3, —CN, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH2CH2CH3, C(O)NHCH2CH3, C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)OCH2CH3, C(O)C(CH3)3, SO2CH3, SO2CH2CH3, SO2CH2CH2CH3, SO2CH(CH3)2, SO2CH(CH3)CH2CH3, SO2N(CH3)2, SO2N(CH3)CH2CH3, OCH3, OCH2CH3, OCH(CH3)2, OCH(CH3)CH2CH3, SCH3, SCH2CH3, SCH(CH3)2, SCH(CH3)CH2CH3, SCH(CH2CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)CH2CH3, N(CH2CH3)CH2CH2CH3, NHC(O)CH3, NHC(O)CH2CH3, NHC(O)CH(CH3)2, NHC(O)CH(CH3)CH2CH3, C(O)NHSO2CH3, C(O)NHSO2CH2CH3, NHC(O)N(CH3)2, NHC(O)N(CH3)CH2CH3, C(S)CH3, C(S)CH2CH3, NHC(S)N(CH3)2, NHC(S)N(CH3)CH2CH3, C(S)OCH3, and NHC(O)CH3;
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, C56 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)r—C3-10 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; and,
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 selected from formula Ib and Ic, wherein:
the central lactam ring is substituted with 0–1 R1a;
G is selected from:


































G1 is selected from (CH2)2-4, (CH2)uC(O)(CH2)w, (CH2)uC(O)O(CH2)w, (CH2)uOC(O)(CH2)w, (CH2)uO(CH2)w,(CH2)w,(CH2)uNR3b(CH2)w, (CH2)uC(O)NR3b(CH2)w, (CH2)uNR3bC(O)(CH2)w, (CH2)uOC(O)NR3b(CH2)w, (CH2)uS(CH2)w, (CH2)uS(O)(CH2)w, (CH2)uS(O)2(CH2)w, (CH2)uS(O)NR3b(CH2)w, (CH2)uNR3bS(O)2(CH2)w, (CH2)uS(O)2NR3b(CH2)w, and (CH2)uNR3e(CH2)w, wherein u+w total 1, 2, or 3 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;
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, SO2NR3R3a, 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, tetrahydropyranyl, 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;
alternatively, when A is selected from one of the following carbocyclic and heterocyclic groups, which are substituted with 0–2 R4c, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, hexahydropyrimidyl, pyrrolidinyl, morpholinyl, and piperazinyl;
then Y is additionally selected from methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 1,1-dimethyl-1-ethyl, 1-pentyl, 2-pentyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH(CF3)2, CH(CHF2), CH(CH2F), CH2CF3, CH(CF2CF3)2, —CN, C(O)NHCH2CH3, C(O)N(CH3)2, C(O)CH2CH2CH3, C(O)C(CH3)3, N(CH3)2, N(CH2CH3)2, NHC(O)CH2CH3, NHC(O)CH(CH3)2, SO2CH3, C(O)NHSO2CH3, C(O)NHSO2CH2CH3, NHC(O)N(CH3)2, NHC(O)N(CH3)CH2CH3, C(S)CH3, C(S)CH2CH3, NHC(S)N(CH3)2, NHC(S)N(CH3)CH2CH3, C(S)OCH3, and NHC(O)CH3;
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 of formula Ic:




or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

the central lactam ring is substituted with 0–1 R1a;
G is selected from:










G1 is selected from (CH2)3, CH2C(O)CH2, CH2C(O)O, CH2OC(O), CH2OCH2, CH2NR3bCH2, CH2C(O)NR3b, CH2NR3bC(O), CH2SCH2, CH2S(O)CH2, CH2S(O)2CH2, CH2S(O)NR3b, CH2NR3bS(O)2, and CH2S(O)2NR3b, wherein u+w total 1, 2, or 3 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;
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 the lactam nitrogen 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(Q)2—, —NHC(O)—, —N(CH3)C(O)CH2—, —C(O)NH—, —CH2NH—, O, and —CH2O—;
Y is selected from N(CH3)2, C(O)(CH3)2, C(CH3)2R4a, (CH2CH3)2R4a, C(O)N(CH3)2, and SO2N(CH3)2;
alternatively, Y is selected from phenyl, pyridyl, pyrrolidino, N-pyrrolidino-carbonyl, morpholino, tetrahydropyranyl, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, and benzimidazolyl, and is substituted with 1 R4a and 0–1 R4;
alternatively, when A is selected from cyclopentyl, cyclohexyl, piperidinyl, and piperazinyl, then Y is additionally selected from methyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 2-butyl, 1,1-dimethyl-1-ethyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, —CN, CH(CF3)2, CH(CHF2), CH(CH2F), CH2CF3, CH(CF2CF3)2, C(O)N(CH3)2, N(CH3)2, and SO2CH3;
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 o,f: 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 fifth embodiment, the present invention provides a novel compound of formula Ic, wherein:
G is selected from:







G1 is selected from CH2NHC(O), and CH2S(O)2NH, wherein 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;
A is selected from the group: cyclohexyl, piperidinyl, 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 the lactam nitrogen 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, C(CH2CH3)2R4a, C(O)N(CH3)2, and SO2N(CH3)2;
alternatively, Y is selected from phenyl, pyridyl, 1,2,3-triazolyl, imidazolyl, morpholino, and benzimidazolyl, and is substituted with 1 R4a;
alternatively, A–B is selected from 4-(2-propyl)-cyclohexyl, 4-(2-propyl)-piperazinyl, 4-(2-propyl)-piperidinyl, 4-(N,N-dimethylamino)-cyclohexyl, 4-(N,N-dimethylamino)-piperazinyl, 4-(N,N-dimethylamino)-piperidinyl, N-methyl-piperdin-4-yl, N-ethyl-piperdin-4-yl, N-(1-propyl)-piperdin-4-yl, N-(2-butyl)-piperdin-4-yl, N-(1,1-dimethyl-ethyl)-piperdin-4-yl, N-(2-methyl-1-propyl)-piperdin-4-yl, N-(N,N-dimethylamido)-piperdin-4-yl, N-(methyl-sulfonyl)-piperdin-4-yl, N-(cyclopropyl)-piperdin-4-yl, N-(cyclobutyl)-piperdin-4-yl, N-(cyclopentyl)-piperdin-4-yl, N-(tetrahydropyranyl)-piperdin-5-yl, N-(1,3-difluoro-2-propyl)-piperdin-4-yl, N-(cyano)-piperdin-4-yl, N-(di-trifluoromethyl-methyl)-piperdin-4-yl, N-(3-pentyl)-piperdin-4-yl, 4-((CH3)2NCH2C(O)N(CH3))-phenyl, and 4-((N-pyrrolidinyl)CH2C(O)N(CH3))-phenyl;
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, wherein:
A is selected from the group: piperidinyl, phenyl, 2-pyridyl, 2-pyrimidyl, and 2-F-phenyl, wherein B is substituted at the 4-position of A;
B is selected from:







alternatively, A–B is selected from 4-(2-propyl)-cyclohexyl, 4-(2-propyl)-piperazinyl, 4-(2-propyl)-piperidinyl, 4-(N,N-dimethylamino)-cyclohexyl, 4-(N,N-dimethylamino)-piperazinyl, 4-(N,N-dimethylamino)-piperidinyl, N-methyl-piperdin-4-yl, N-ethyl-piperdin-4-yl, N-(1-propyl)-piperdin-4-yl, N-(2-butyl)-piperdin-4-yl, N-(1,1-dimethyl-ethyl)-piperdin-4-yl, N-(2-methyl-1-propyl)-piperdin-4-yl, N-(N,N-dimethylamido)-piperdin-4-yl, N-(methyl-sulfonyl)-piperdin-4-yl, N-(cyclopropyl)-piperdin-4-yl, N-(cyclobutyl)-piperdin-4-yl, N-(cyclopentyl)-piperdin-4-yl, N-(tetrahydropyranyl)-piperdin-5-yl, N-(1,3-difluoro-2-propyl)-piperdin-4-yl, N-(di-trifluoromethyl-methyl)-piperdin-4-yl, N-(cyano)-piperdin-4-yl, N-(3-pentyl)-piperdin-4-yl, N-(2-pyridyl)-piperdin-4-yl, and 4-((N-pyrrolidinyl)CH2C(O)N(CH3))-phenyl;
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, wherein:
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, CR2CH3, 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 selected from: Examples 1–2 or a pharmaceutically acceptable salt form thereof.
In a ninth embodiment, the present invention provides a novel compound selected from formula Id and Ie:




or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

one of T1 and T2 is selected from C(O) and S(O)2 and the other is selected from C(O), S(O)2, CH2 and CHOH;
one of Z1 and Z2 is N and the other is C;
G is a group of formula IIa or IIb:




ring D, including the two atoms of ring E to which it is attached, is a 5–6 membered ring consisting of: carbon atoms and 0–2 heteroatoms selected from the group consisting of N, O, and S(O)p;
ring D is substituted with 0–2 R and there are 0–3 ring double bonds;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1–2 R;
alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1–2 R;
alternatively, ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is substituted with a 5 membered heterocycle consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5 membered heterocycle is substituted with 0–1 carbonyls and 1–2 R and has 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, 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, and OCF3;
alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
G1 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)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)uC(O)NR3bS(O)2(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3b(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(S)NR3b(CR3R3a)w, and (CR3R3a)uNR3bC(S)(CR3R3a)uC(O)NR3b(CR3R3a)w, wherein u+w or u+u+w total 0, 1, or 2 and 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: 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 the lactam nitrogen 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—CR4c=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, SO2R3, and C(O)NR3R3a;
Y1 and Y2 are independently C13 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, cyclobutyl, 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, isoindazolyl, 4,5-dihydroimidazolyl, 1,4,5,6-tetrahydropyrimidinyl, and, [1,4]diazepanyl;
alternatively, when A is selected from one of the following carbocyclic and heterocyclic groups, which are substituted with 0–2 R4c, cyclohexyl, cyclopentyl, azetidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, morpholinyl, and pyrrolidinyl;
then Y is additionally selected from methyl, ethyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1,1-dimethyl-1-ethyl, 1-pentyl, 2-pentyl, 3-pentyl, 3-hexyl, CH(CF3)2, CH(CHF2)CH3, CH2CF3, CH(CF2CF3)2, CH(Cl)CF3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH2CH2CH3, C(O)NHCH2CH3, C(O)N(CH3)2, C(O)N(CH3)(CH2CH3), C(O)OCH2CH3, C(O)C(CH3)3, SO2CH3, SO2CH2CH3, SO2CH2CH2CH3, SO2CH(CH3)2, SO2CH(CH3)CH2CH3, SO2N(CH3)2, SO2N(CH3)CH2CH3, OCH3, OCH2CH3, OCH(CH3)2, OCH(CH3)CH2CH3, SCH3, SCH2CH3, SCH(CH3)2, SCH(CH3)CH2CH3, SCH(CH2CH3)2, N(CH3)2, N(CH2CH3)2, N(CH3)CH2CH3, N(CH2CH3)CH2CH2CH3, NHC(O)CH3, NHC(O)CH2CH3, NHC(O)CH(CH3)2, and NHC(O)CH(CH3)CH2CH3;
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)rC3lo 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 selected from formula Id1-8 and Ie1-8:







or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is selected from: 2-aminomethyl-4-chloro-phenyl, 2-aminosulfonyl-4-chloro-phenyl, 2-amido-4-chloro-phenyl, 4-chloro-2-methylsulfonyl-phenyl, 2-aminosulfonyl-4-fluoro-phenyl, 2-amido-4-fluoro-phenyl, 4-fluoro-2-methylsulfonyl-phenyl, 2-aminomethyl-4-bromo-phenyl, 2-aminosulfonyl-4-bromo-phenyl, 2-amido-4-bromo-phenyl, 4-bromo-2-methylsulfonyl-phenyl, 2-aminomethyl-4-methyl-phenyl, 2-aminosulfonyl-4-methyl-phenyl, 2-amido-4-methyl-phenyl, 2-methylsulfonyl-4-methyl-phenyl, 4-fluoro-pyrid-2-yl, 4-bromo-pyrid-2-yl, 4-methyl-pyrid-2-yl, 5-fluoro-thien-2-yl, 5-bromo-thien-2-yl, 5-methyl-thien-2-yl, 2-amido-4-methoxy-phenyl, 2-amido-phenyl, 2-aminomethyl-3-fluoro-phenyl, 2-aminomethyl-4-fluoro-phenyl, 2-aminomethyl-4-methoxy-phenyl, 2-aminomethyl-5-fluoro-phenyl, 2-aminomethyl-5-methoxy-phenyl, 2-aminomethyl-6-fluoro-phenyl, 2-aminomethyl-phenyl, 2-amino-pyrid-4-yl, 2-aminosulfonyl-4-methoxy-phenyl, 2-aminosulfonyl-phenyl, 2-methylsulfonyl-phenyl, 3-(N,N-dimethylamino)-4-chloro-phenyl, 3-(N,N-dimethylamino)-phenyl, 3-(N-methylamino)-4-chloro-phenyl, 3-(N-methylamino)-phenyl, 3-amido-phenyl, 3-amino-4-chloro-phenyl, 3-aminomethyl-phenyl, 3-amino-phenyl, 3-chloro-phenyl, 4-(N,N-dimethylamino)-5-chloro-thien-2-yl, 4-(N-methylamino)-5-chloro-thien-2-yl, 4-amino-5-chloro-thien-2-yl, 4-chloro-phenyl, 4-methoxy-2-methylsulfonyl-phenyl, 4-methoxy-phenyl, 2-methoxy-pyrid-5-yl, 5-(N,N-dimethylamino)-4-chloro-thien-2-yl, 5-(N-methylamino)-4-chloro-thien-2-yl, 5-amino-4-chloro-thien-2-yl, 5-chloro-pyrid-2-yl; 5-chloro-thien-2-yl, 6-amino-5-chloro-pyrid-2-yl, 6-amino-pyrid-2-yl, 2-cyano-4-chloro-phenyl, 2-methoxy-4-chloro-phenyl, 2-fluoro-4-chloro-phenyl, phenyl; 4-ethyl-phenyl, 3-chloro-4-methyl-phenyl, 4-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-fluoro-4-methyl-phenyl, 3,4-dimethyl-phenyl, 3-chloro-4-fluoro-phenyl, 3-methyl-4-fluoro-phenyl, 4-methylsulfanyl-phenyl, 2-chlorothiazol-5-yl, 5-chlorothiazol-2-yl,






















G1 is selected from CH2, CH2CH2, CH═CH, CH2O, OCH2, C(O), NH, CH2NH, NHCH2, CH2C(O), C(O)CH2, C(O)NH, NHC(O), NHC(O)NH, NHC(O)CH2C(O)NH, C(O)NHS(O)2, CH2S, SCH2, CH2S(O), S(O)2, CH2S(O)2, S(O)2(CH2), SO2NH, NHSO2, NHCH2C(O)NH, NHC(O)C(O)NH, NHC(O)C(S)NH, and NHC(S)C(O)NH and 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, SO2R3, 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: cyclopropyl, cyclobutyl, 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, isoindazole, 4,5-dihydro-2-imidazolyl, 1,4,5,6-tetrahydro-2-pyrimidinyl, and, [1,4]diazepanyl;
alternatively, when A is selected from one of the following carbocyclic and heterocyclic groups, which are substituted with 0–2 R4c, cyclopentyl, cyclohexyl, piperidinyl, hexahydropyrimidyl, pyrrolidinyl, and piperazinyl;
then Y is additionally selected from methyl, ethyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-pentyl, CH(CF3)2, CH(CHF2)CH3, CH2CF3, CH(CF2CF3)2, C(O)NHCH2CH3, C(O)N(CH3)2, C(O)CH2CH2CH3, C(O)C(CH3)3, N(CH3)2, N(CH2CH3)2, NHC(O)CH2CH3, NHC(O)CH(CH3)2, and SO2CH3,
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(Q)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 an eleventh embodiment, the present invention provides a novel compound selected from formula Id1.1-8.1 and Ie1.1-8.1:







or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

G is selected from: phenyl, 4-ethyl-phenyl, 2-aminomethyl-4-chloro-phenyl, 2-aminosulfonyl-4-chloro-phenyl, 2-amido-4-chloro-phenyl, 4-chloro-2-methylsulfonyl-phenyl, 2-aminosulfonyl-4-fluoro-phenyl, 2-amido-4-fluoro-phenyl, 4-fluoro-2-methylsulfonyl-phenyl, 2-aminomethyl-4-bromo-phenyl, 2-aminosulfonyl-4-bromo-phenyl, 2-amido-4-bromo-phenyl, 4-bromo-2-methylsulfonyl-phenyl, 2-aminomethyl-4-methyl-phenyl, 2-aminosulfonyl-4-methyl-phenyl, 2-amido-4-methyl-phenyl, 2-methylsulfonyl-4-methyl-phenyl, 4-fluoro-pyrid-2-yl, 4-bromo-pyrid-2-yl, 4-methyl-pyrid-2-yl, 5-fluoro-thien-2-yl, 5-bromo-thien-2-yl, 5-methyl-thien-2-yl, 2-amido-4-methoxy-phenyl, 2-amido-phenyl, 2-aminomethyl-3-fluoro-phenyl, 2-aminomethyl-4-fluoro-phenyl, 2-aminomethyl-5-fluoro-phenyl, 2-aminomethyl-6-fluoro-phenyl, 2-aminomethyl-phenyl, 2-amino-pyrid-4-yl, 2-aminosulfonyl-4-methoxy-phenyl, 2-aminosulfonyl-phenyl, 3-amido-phenyl, 3-amino-4-chloro-phenyl, 3-aminomethyl-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-methoxy-phenyl, 2-methoxy-pyrid-5-yl, 5-chloro-pyrid-2-yl, 5-chloro-thien-2-yl, 6-amino-5-chloro-pyrid-2-yl, 6-amino-pyrid-2-yl, 2-cyano-4-chloro-phenyl, 2-methoxy-4-chloro-phenyl, 2-fluoro-4-chloro-phenyl, 3-chloro-4-methyl-phenyl, 4-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-fluoro-4-methyl-phenyl, 3,4-dimethyl-phenyl, 3-chloro-4-fluoro-phenyl, 3-methyl-4-fluoro-phenyl, 4-methylsulfanyl-phenyl, 2-chlorothiazol-5-yl, 5-chlorothiazol-2-yl,



















G1 is selected from CH═CH, CH2C(O), C(O)CH2, NH, C(O)NH, NHC(O), CH2S, SCH2, CH2S(O), CH2SO2, SO2NH, NHSO2 NHCH2C(O)NH, NHC(O)C(O)NH, NHC(O)C(S)NH, and NHC(S)C(O)NH and 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 the lactam nitrogen 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 5–7 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, SO2(CH3), SO2(CH2CH3), C(O)N(CH3)2, C(CH3)2R4a and C(CH2CH3)2R4a;
alternatively, Y is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrrolidino, N-pyrrolidino-carbonyl, morpholino, N-morpholino-carbonyl, 1,2,3-triazolyl, imidazolyl, benzimidazolyl, 4,5-dihydro-2-imidazolyl, 2-pyrrolidin-1-yl-methyleneamine, 2-piperidin-1-yl-methyleneamine, 2-morpholin-4-yl-methyleneamine, 1,4,5,6-tetrahydro-2-pyrimidinyl, [1,4]diazepanyl, piperdinyl, pyrrolidinyl, and morpholinyl, and is substituted with 1 R4a and 0–1 R4;
alternatively, when A is selected from and piperidinyl, then Y is additionally 2-propyl;
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, (CR3R3g)r—SO2NR2dR2d, 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, wherein:
G is selected from:










G1 is selected from CH2NH, C(O)NH, NHC(O), CH2S, CH2S(O), CH2SO2, NHCH2C(O)NH, NHC(O)C(O)NH, and 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, 4-piperdinyl, 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 the lactam nitrogen 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)N(CH3)2, C(CH3)2R4a and C(CH2CH3)2R4a;
alternatively, Y is selected from phenyl, pyridyl, 1,2,3-triazolyl, imidazolyl, N-pyrrolidino-carbonyl, N-morpholino-carbonyl, benzimidazolyl, 4,5-dihydro-2-imidazolyl, 2-pyrrolidin-1-yl-methyleneamine, 2-piperidin-1-yl-methyleneamine, 2-morpholin-4-yl-methyleneamine, 1,4,5,6-tetrahydro-2-pyrimidinyl, [1,4]diazepanyl, pyrrolidinyl, and morpholinyl, and is substituted with 1 R4a;
alternatively, A-B is selected from 4-(2-propyl)-piperidinyl and 4-(N,N-dimethylamino)-piperidinyl;
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, (CH2)r—SO2NR2dR2d, 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 selected from formula Id1.1-3.1 and Ie1.1-3.1:




wherein:

G is selected from:







G1 is CH2NH, C(O)NH, NHC(O), NHC(O)C(O)NH, and the right side of G1 is attached to ring G;
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:










alternatively, A—B is selected from 4-(2-propyl)-piperidinyl and 4-(N,N-dimethylamino)-piperidinyl;
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, SO2NR2dR2d, CH2SO2NR2dR2d, 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 selected from formula Id1.1 and Ie1.1:




wherein:

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)NR2, 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 selected from Examples 3–6 or a pharmaceutically acceptable salt thereof.
In a sixteenth embodiment, the present invention provides a novel compound selected from the Examples of Table 1 and Table 2 or a pharmaceutically acceptable salt 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 form thereof.
In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
In another preferred embodiment, the present invention provides a novel method, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
In another embodiment, the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
In another embodiment, the present invention provides a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is compound of the present invention or a pharmaceutically acceptable salt thereof and the second therapeutic agent is at least one agent selected from a second factor Xa inhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent.
In another preferred embodiment, the present invention provides a novel method, wherein the second therapeutic agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfmpyrazone, 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:

    
    
        (a) (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). 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.
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, sulfric, 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.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. “Prodrugs” are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that there presently recited compounds do not contain a N-halo, S(O)2H, or S(O)H group.
“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.
As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
“Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit factor Xa. “Therapeutically effective amount” is also intended to include an amount of the combination of compounds claimed that is effective to inhibit factor Xa. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27–55, occurs when the effect (in this case, inhibition of factor Xa) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antithrombotic effect, or some other beneficial effect of the combination compared with the individual components.
Synthesis
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. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). Examples of suitable blocking groups and their uses are also 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 having the general structures of formula Ia, Ib, or Ic can be prepared as shown in schemes 1–15. For example, as shown in Scheme 1, an appropriately amine and itaconic acid 1a can be converted to 1b under refluxed condition in toluene (J. Org. Chem., 1980, 45, 810). Reduction of the acid group to hydroxyl followed by a standard three-step conversion of hydroxyl to amino group, should provide amine 1d. The formation of desired target can be completed by reacting an appropriately substituted acid, or sulfonyl chloride, or isocyanide.




Compounds of the present invention can also be prepared as outlined in Scheme 2. Reductive amination of 2a with an appropriate amine should provide the corresponding secondary amine, which under reflux condition in an appropriate solvent should yield 2b (Helvetica Chimica Acta, 2002, 85, 4046). Target compounds can be obtained via procedures known to those skilled in the art.




Compounds of the present invention can also be prepared as outlined in Scheme 3, wherein an appropriately substituted imine 3b can react with 3a in the presence of base, such as LiHMDS, to provide the cyclized compound 3c (Terahydron Lett., 1995, 36, 8445). Following similar procedures known to those skilled in the art, the target compounds can be obtained.




Similarly, compounds of the present invention can also be prepared as outlined in Scheme 4. Reductive amination of an appropriate amine with 4a followed by cylization should provide 4b, which can follow procedures similar to those described and known to those of skill in the art to produce target compounds.




Compounds of the present invention can also be prepared as outlined in Scheme 5. Compound 5a can be converted to lactam 5b under acid and base treatments. Then Ullmann or Buchwald reaction should provide 5c, which can be converted to target compounds via procedures described in the art.




Compounds of the present invention with variable ring sizes can be prepared as outlined in Scheme 6. Dienoate 6a can be converted to hydroxyl acid 6b via procedures described by Kishi (Tetrhedron Lett., 1995, 36, 4579). Functional group manipulation and cyclization can give lactam 6d, which under Ullmann or Buchwald condition should yield 6e. Deprotection and acylation or sulfonation should provide the target compounds.




Compounds of the present invention with variable ring sizes are also prepared as outlined in Scheme 7. Treatment of 7a with appropriate amine 7b under coupling conditions should yield compound 7c. Sulfide 7c can be converted to its corresponding sulfonium salt by treatment with methyl iodide, and then to lactam 7d under basic conditions such as K2CO3 or KHMDS. Following the procedures known to those skilled in the art, compounds of the present invention can be obtained. (Tetrahedron 1984, 40, 1433; Organic Lett. 2000, 2, 1101; Klapers et al. JACS, 2001, 123, 7727; Tet. Lett., 1999, 40, 2657).




Compounds of the present invention can also be prepared as outlined in Scheme 8. Acid 6b can be coupled with appropriate amine to give compound 8a. Under Mitsunobu conditions (Mitsunobu, Synthesis, 1981, 1), 8a can be converted to lactam 8b, which can then be converted to a compound of the present invention via procedures known to those skilled in the art.




Alternately, the fully elaborated A—B moiety can be prepared as a heterocyclic amine derivative as shown in Scheme 9. Cyclization of 9a should give heterocycle 9b, which then can be converted to compounds of the present invention via procedures known to those skilled in the art.




A fully elaborated A—B moiety, such as 10b, can also be prepared as shown in Scheme 10, which then can be converted to 10c via procedures known to those skilled in the art.




Ahe fully elaborated A—B moiety, such as 11b and 11c can be prepared as shown in Scheme 11, which then can be converted to 11d and 11e via procedures known to those skilled in the art.




Alternately, compounds of the present invention can be prepared as described in Scheme 12. An appropriately substituted amine 12a can react with an appropriately substituted halogenated acyl chloride to give lactam 12b, which can then be converted to compounds of the present invention via procedures known to those skilled in the art.




A fully elaborated A—B moiety, such as 13c, can be prepared via Ullmann or Buckwald methodology starting from 13a and 13b as shown in Scheme 13. Following similar procedures known to those skilled in the art, the target compound can be obtained.




A fully elaborated A—B moiety, such as 14c, can be prepared as illustrated in Scheme 14. Iodoaniline 14a can be aminated with benzophenone imine using Wolfe method (Tetrahydron Lett. 1997, 38, 6367) to provide the monoprotected diaminobenzene 14b. Acylation with 5-bromovalerylchloride followed by cyclization in the presence of base should give aryllactam 14c, which can be converted to a compound of the present invention via procedures known to those skilled in the art.




A fully elaborated A—B moiety, such as 15b, can be prepared as illustrated in Scheme 15. Ullmann or Buckwald chemistry can also applied to prepared 15b, which can be subsequentially converted to compounds of the present invention via procedures known to those skilled in the art.




Construction of compounds with general structures of formula Id or Ie can be performed in the following direction: from W—A—B (W is NH2, I, Br, etc) to compounds of formula IId or IIe where Rg is a stable group attached to the bicyclic ring during the process of preparing compounds of formula IId or IIe. The Rg group in compounds of formula IId or IIe can be transformed to the “reactive” intermediate of formula IIId or IIIe, and then reacted with compounds of formula IVd or IVe, containing G groups under standard coupling conditions known in the literature and by ones skilled in the art, to provide compounds of formula Id or Ie of the present invention. The general route that involves this type of methodology is outlined in Scheme 1.




Intermediates of formula IId and IIe can be prepared by using the methods described in the following synthetic schemes (Scheme 17 to Scheme 21) from intermediates W—A—B, wherein W is NH2, I, or Br, and by using relevant published literature procedures that are known to those skilled in the art.
As shown in Scheme 17, intermediates of formula IId and IIe (Z1=N, Z2=CH, T1 is C═O or C═S, and T2 is CH2) can be prepared from appropriately protected five-membered or six-membered monocyclic intermediates 16, which can be readily prepared from commercially available materials or by using methods known in the literature and by one skilled in the art. The carboxylic acid intermediate 16 can be treated with a reducing agent, such as BH3 and LiAlH4, to form the alcohol 17, which can then be oxidized to form the aldehyde 18 by using an oxidizing agent, such as Dess-Martin periodinate. Reductive amination of the aldehyde 18 and the amine of formula NH2—A—B in the presence of sodium triacetoxyborohydride can give the intermediate 19. Removing N-protecting group (PG) of 19 can then be achieved by methods known in the literature or by one skilled in the art to give diamino intermediate 20. Intermediate 20 can be treated with phosgene or phosgene equivalent in the presence of a base, such as triethylamine, to provide the compounds of formula IId and IIe. Alternatively, compounds of formula IId and IIe can be obtained from the methyl ester intermediate 21. Urea formation of 21 with isocyanate of formula OCN—A—B in a solvent, such as toluene, tetrahydrofuran, or methylene chloride, with a base, such as triethylamine, can provide the intermediate 22. Treatment of 22 with a reducing agent, such as LiAlH4 or super hydride, can afford the alcohol intermediate 23. Treatment of 23 with an activating agent, such as mesyl chloride or tosyl chloride, in the presence of a base such as potassium tert-butoxide or an equivalent reagent, can generate the compound of formula IId or IIe.




On the other hand, as illustrated in Scheme 18, intermediates of formula IId or IIe (Z1=N, Z2=CH, T1 is C═O or C═S, and T2 is CH2) can also be prepared via an intermediate of formula of W—A—B (wherein W can be I, Br, TfO, etc.) via either Copper(I)-catalyzed Ullmann-type aromatic amination of aryl iodides and aryl bromides, heating in DMSO with either N-methylglycine or L-proline as a ligand (Ma, Dawei, et. al, Organic Letters 2003, 5, 2453–2455); or ethylene glycol as the ligand while heating in 2-propanol (Buchwald, S. L., et al., Organic Letter 2002, 4, 581–584); or via Pd(0)-catalyzed amination of aryl iodides in the presence of palladium (such as Pd2(dba)3), a suitable ligand (such as 1,1′-biphenyl-2-yldicyclohexylphosphine), and NaOt-Bu (Buchwald, S. L. et. al., Journal of Organic Chemistry 2001, 66, 2560–2565). Thus, alcohol intermediate 17 can be translated to an azide intermediate 24 by first activating the alcohol with mesyl chloride, etc , and then reacting with sodium azide. Reduction of the azide 24 to the primary amine 25 can be carried out either by hydrogenation or by using PPh3/THF/H2O conditions.
The primary amine 25 can react with the compounds of formula W—A—B in the presence of a palladium catalyst to afford the intermediate of formula 26. N-deprotection of 26 can be achieved by methods known in the literature or by one skilled in the art to give diamino intermediate 27. The intermediate 27 can be treated with phosgene or phosgene equivalent in the presence of a base, such as triethylamine, to provide the intermediates of formula IId or IIe. Alternatively, intermediate 28 bearing a L group (such as phenyl or benzyl group) as a protecting group can be prepared as discussed previously. Deprotection of L by hydrogenation under high pressure can afford the intermediate 29, which can be reacted with compound of formula W—A—B (wherein W is I or Br) in the presence of Pd(0) or under Ullman coupling conditions to provide the intermediates of formula IId or IIe of the present invention.







Scheme 4 shows the preparation of intermediates of formula IId or IIe when Z1=N, Z2=C, T1 is C═O or C═S, and T2 is C═O. Treatment of methyl ester 21 with an isocyanates or thioisocyanates of formula X═C═N—A—B can afford intermediate 30, which can be treated with a base, such as DBU, to yield intermediates of formula IId or IIe. On the other hand, hydrolysis of the methyl ester in intermediate 22 using NaOH to give the acid 31, which is treated with a suitable coupling reagent such as DCC, can also form intermediates of formula IId or IIe of the present invention.




Scheme 20 shows the preparation of intermediates of formula IId and IIe (Z1=N, Z2=C, T1 is SO2, and T2 is C═O or CH2) starting from the diamine intermediate 20.




Scheme 21 also depicts the preparation of intermediates of formula IId and IIe (Z1=C, Z2=N, T1 is CH2, and T2 is C═O.)




Scheme 22 describes general methods of converting the intermediate of formula IId or IIe to compounds of the present invention of formula Id or Ie wherein linker G1 can be —NHCO—, —NHCOCONH—, —NHCOC(S)NH—, —NHC(S)CONH—, —NHSO2—, or —NHCH2—. The intermediates of formula IId or IIe where Rg is a properly protected alcohol can be obtained by the methods described in schemes 17–23 and by those skilled in the art. O-deprotection can be achieved by known literature method or by those skilled in the art. The alcohol intermediate 34 can be activated and then displaced with NaN3 to afford the azide intermediate 35, which under reduction gives the amine intermediate 36. Coupling of the amine 36 with a variety of reagents containing the G group can provide a variety of compounds of formula Id or Ie.




A series of compounds of the present invention of formula Id or Id wherein G1 is 1,1-dioxo-sulfonylmethyl can be prepared following the sequence outlined in Scheme 23.




The functionalized G moiety of the present invention 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, 6,339,099, 6,271,237, 6,399,644, 6,407,256, 6,413,980, WO02/00651, WO02/102380, WO02/094197, U.S. 2003/78,255, and U.S. 2003/18,023 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. Nos. 5,998,424, 6,413,980, 6,399,644, 6,407,256, WO02/00651, WO02/102380, WO02/094197, U.S. 2003/78,255, and U.S. 2003/18,023 for starting materials. For compounds wherein G is a bicyclic moiety, one of ordinary skill in the art can look to U.S. Pat. Nos. 6,339,099, 6,369,227, 6,413,980, WO02/00651, WO02/102380, WO02/094197, U.S. 2003/78,255, and U.S. 2003/18,023 for starting materials. For compounds wherein A is an indoline or similar bicycle, one of ordinary skill in the art can look to U.S. Pat. No. 6,429,205 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.
The A—B intermediates of the present invention wherein A is a substituted phenyl and B is




wherein Q4 is CO or SO2, and Q3 is a 5–7 membered ring containing 0–1 hetero atom, can be prepared by methods shown in Scheme 24–29 and by those skilled in the art.

The A—B intermediates can be obtained via the Ullman reaction or Buchwald modified Ullman reaction (J. Am. Chem. Soc. 2001, 123, 7727) using CuI and 1,2-cyclohexyldiamine or 1,10-phenanthroline as the catalyst as outlined in Scheme 24.




The Ullman coupling methodology can also be applied to prepare the cyclic urea or cyclic carbamate analogs shown in Scheme 25.




The lactam A—B group can also be prepared via aromatic nucleophile displacement of substituted halo-nitrobenzenes followed by reduction and other transformations as shown in Scheme 11.




The lactam containing A—B intermediates can also be prepared via aromatic nucleophilic substitution of fluoronitrobenzenes with the 5–7 membered bases followed by α-carbon oxidation with KMnO4 as shown in Scheme 27.




Lactam, cyclic sulfonamide, cyclic urea, and cyclic carbamate A—B analogs can be prepared via the method outlined in Scheme 28.




The piperidone A—B groups shown above can also be further elaborated to afford other compounds of the present invention by numerous methods known to those skilled in the art as shown in Scheme 29.




Ortho-substituted pyridyl and pyrimidyl A—B analogs wherein B is a lactam-containing group (see structures in Scheme 30), can also be prepared using routes similar to those of Schemes 24–29.







The non-aromatic A—B intermediates in Scheme 16 wherein A is a cyclohexyl ring and B is a lactam ring, can be synthesized via procedures known to those skilled in the art. These intermediates can than be further manipulated to incorporate substituent R4 via procedures previously described.




Compounds of the present invention wherein Y is N(B1)C(O)C(R3R3g)2-4NB2B3 can be made as described in Schemes 32–34. Scheme 32 describes the syntheses of A—B intermediate via Buchwald Ullman 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)2-4NB2B3 can also be prepared from readily available anilines as shown in Scheme 33.




Aminopyridyl, aminopyrimidyl, indonyl, cyclohexyl, and piperidinyl A—B analogs containing NH(B1)C(O)C(R3R3g)2-4NB2B3 (see structures in Scheme 34) can be prepared using routes similar to those of Schemes 31–33 and by those known in the art.




A—B intermediates of the present invention wherein B is an amidino derivative can be prepared following the general procedure outlined in Schemes 35–40. A—B intermediates of the present invention wherein B is a cyclic amidino derivative with one of the nitrogen atoms of the aminido group linked to the A ring, can be prepared as shown in Scheme 20. Boc-protection of the aniline followed by alkylation with chloro iodoalkane 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.




The diamino intermediate from Scheme 35 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 can be achieved using the methods described in Scheme 36 and by those known in the art.




The guanidino A—B derivative from Scheme 36 can be converted to a number of A—B intermediates of the present invention by techniques known to those of skill in the art of organic synthesis, as outlined in Scheme 37.




Using the methodologies outlined above, other compounds of the present invention can be obtained as shown in Scheme 38 by functional manipulations and cyclization techniques known to those of skill in the art of organic synthesis.




Phenylamidino-sulfonyl and -carbonyl A—B intermediates of the present invention can be obtained from the readily available amidino compounds shown in Scheme 39 below.




Other A—B intermediates of the present invention wherein B is a cyclic amidino derivative with the carbon atom of the amidino group linked to the A ring can be prepared using properly protected aryl nitriles as the starting material as illustrated in Scheme 40. The pinner reaction (MeOH, HCl), followed by displacement with a diamine can provide protected A—B precursor, which can be transformed to A—B intermediates of the present invention using methods described previously and by those skilled in the art. Alternatively, iodination will provide the desired para-substituted intermediate, which can in turn be transformed to the amino A—B intermediate via Buchwald palladium-catalyzed amination (Tetrahedron Lett. 1997, 38, 6367–6370).




Other A—B intermediates of the present invention containing a substituted biaryl or a substituted aryl-heteroaryl can be prepared as shown in Scheme 41. They can be obtained by reacting a boronic acid with a properly protected 4-bromobenzene under Suzuki coupling conditions.




Other A—B intermediates of the present invention wherein B is an imidazole derivative can be prepared as shown in Scheme 42, using Ullman or Buchwald modified Ullman reaction conditions (J. Am. Chem. Soc. 2001, 123, 7727) using CuI and 1,2-cyclohexyldiamine, or N,N-dimethylethylene diamine, or 1,10-phenanthroline.




Other A—B intermediates of the present invention wherein B is a [1,4]diazepane derivative can be prepared using the procedures shown in Scheme 43. Aromatic nucleophilic displacement or C—N bond formation using Pd(0) chemistry should provide the A—B intermediate.




A—B intermediates wherein B is X—Y, X is a 1–3 atom linker, and Y is a heteroaryl or aryl derivative can also be prepared as described previously in WO 98/06694, U.S. Pat. No. 6,057,342, WO 98/28282, U.S. Pat. No. 6,187,797, WO 98/28269, U.S. Pat. No. 6,020,357, WO 98/57934, and U.S. Pat. No. 6,426,346 and by methods known to those skilled in the art.
Aminopyridyl and aminopyrimidyl A—B analogs (see Scheme 44) can be prepared using routes similar to those of Schemes 35–43 and also by those skilled in the art. These intermediates can then be manipulated to compounds of the present invention via procedures previously described.




A—B intermediates of the present invention wherein B is




(provided that A and R4a are attached to the same carbon atom in Q5, and Q5 is C3–C7 cycloalkyl) can be prepared as shown in Scheme 45. Commercially available 4-nitrophenylacetonitrile (or properly protected 4-aminophenylacetonitrile) can be used as the starting material. Alkylation with NaH, KtOBu, 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 37. Hydrolysis of the nitrile group, followed by reduction of the ester group can provide the alcohol 38. Oxidation of 38, then reductive amination with NHR2R2d can provide 39. Reduction of the nitro group or deprotection of the amino-group can produce the A—B precursor 40. When one of the R2 and R2d group is H, 40 can react with acid chlorides, carbamoyl chlorides, sulfonyl chlorides, and isocyanates to provide A—B intermediates of the invention with structures 41, 42, 43, and 44. Alternatively, alcohol 38 can react with alkyl halides and amines to form compounds of the invention with structures 45 and 46. Alcohol 38 can also be transferred into a halide or its equivalents (X=Cl, Br, I, OMs, or OTs), followed by alkylation with a variety of alkylating reagents to afford A—B intermediates of the present invention with structures 47, 48, and 49.








Other A—B intermediates of the present invention wherein Q5 is a cycloalkyl derivative can be prepared using commercially available 1-phenylcycloalkylcarboxylic acids (or 1-phenylcycloalkylcarbonitriles) as the starting materials as illustrated in Scheme 46. Thus, nitration, followed by reduction of the NO2 group and protection of the acid group can provide the A—B precursor 50.
Alternatively, iodination can provide the desired para-iodo compound 51, which can in turn be transformed to the amine 52 via Buchwald palladium-catalyzed amination (Tetrahedron Lett. 1997, 38, 6367–6370) and to the acid 53 via palladium-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 52 and 53, respectively.




Other compounds of the present invention wherein Q5 is a cycloalkyl derivative can be prepared using organometalic reagents (Zn, Mg, etc) 54 as starting materials as shown in Scheme 32. Reaction of 54 with properly substituted cycloalkyl halides 55 (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 56. Alternatively, Grignard reaction of 54 with cycloalkyl ketones can provide intermediate 57. Further elaboration of 56 and 57 using the methods described above and by those known in the art should provide A—B intermediates of the present invention.




A—B intermediates of the present invention wherein Q5 is a pyrrolidine or piperidine derivative can be prepared as shown in Scheme 48. Thus, phenylcyanoacetate can be alkylated with X—(CH2)n—Cl (X and Y=Br, I, OMs, OTs, etc and n=2–3) to provide the chloronitrile 58, which can be reduced to the corresponding primary amine, followed by cyclization in refluxing EtOH to form 3-pyrrolidine or 3-piperdine derivatives 59. Alkylation or reductive amination can provide the N-substituted intermediate 60. Further elaboration using the methods described above and by those known in the art should provide A—B intermediates of the present invention.




A—B intermediates of the present invention wherein Q5 is a 4-piperidine derivative or tetrahydropyran derivative can be prepared using 2-aryl acetonitriles 61 as starting materials as shown in Scheme 49. Dialkylation of 61 with bromoacetaldehyde dimethyl acetal, followed by hydrolysis of the acetals and reductive amination can give the 4-aryl-4-cyanopiperidine 62. Alkylation of 61 with di-2-chloroethyl ether can give the 4-aryl-4-cyanotetrahydropyran 63.




A—B intermediates of the present invention wherein Q5 is a 4-tetrahydrofuran derivative can be prepared using diol 64 as the starting material as illustrated in Scheme 50. Cyclization of 64 with HBr will give the 4-aryl-4-substituted tetrahydrofuran 65. Further elaboration using the methods described above and by those known in the art should provide A—B intermediates of the present invention.




A—B intermediates of the present invention wherein Q5 is a lactam derivative can be prepared using intermediate 66 as the starting material as shown in Scheme 51. Reduction of NO2 group or nitrile group can provide the primary amine 67, which can be coupled intramolecularly with the acid or ester to form the lactam 68. Further elaboration using the methods described above and by those known in the art should provide A—B intermediates of the present invention.




A—B intermediates of the present invention wherein Q5 is a carbocycle or heterocycle and R4a is CH2CH2NR2dR2d or CH2CONR2dR2d can be prepared as outlined in Scheme 52, and via standard methods known to those skilled in the art. The ester or nitrile intermediates 69 can be subjected to alkylation conditions, followed by other manipulations as described in Schemes 45–51 to form 70. Homologation of intermediates 70 with TMSCHN2 as the reagent can afford 71. Further elaboration of 71 to form 72 and A—B intermediates of the present invention can be achieved using the methods described above and by those known in the art.




A—B intermediates of the present invention wherein Q5 is a carbocycle or heterocycle and R4a is NR2dR2d can be prepared as outlined in Scheme 53 and via standard methods known to those skilled in the art. The acid intermediates 70 illustrated in Scheme 52 can undergo Curtius rearrangement with DPPA in CH2Cl2 followed by heating in t-BuOH to afford Boc-protected cyclopropylamine intermediates 73. Alkylation of 73 with R2d—I and NaH in THF followed by manipulations described previously will give amines 74. Reductive amination of 74 with aqueous formaldehyde and NaBH3CN in CH3CN can afford the methyl alkyl amine analogues of A—B intermediates. On the other hand, alkylation of the amine 75 with a dibromide using K2CO3 as the base can afford A—B intermediates bearing tertiary or cyclic amines, respectively.




Schemes 45–53 describe how to make the A—B moieties of the present invention wherein B is




and Q5 is a cycloalkyl or heterocyclyl. A—B moieties of the present invention wherein B is YR4a and Y is CY1Y2 can be made analogously to the cycloalkyl/heterocyclyl compounds of Schemes 45–53. For example, in Scheme 45, instead of intermediate 37 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 intermediate are available. In Scheme 46, instead of use the starting 1-phenylcycloalkylcarboxylic acids or 1-phenylcycloalkylcarbonitriles, one could use the corresponding Y1Y2 disubstituted intermediates. Just like in Scheme 45, 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 46 will then follow.

Aminopyridyl, aminopyrimidyl, cyclohexyl, and piperidinyl A—B analogs wherein B is




and Q5 is a cycloalkyl or heterocyclic groups, as well as aminopyridyl, aminopyrimidyl, cyclohexyl, and piperidinyl A—B analogs wherein B is Y—R4a and Y is geminal dimethyl group (see structures in Scheme 54), can be prepared using routes similar to those of Schemes 45–53 and by those known in the art.








As shown in Scheme 55, additional A—B intermediates can be synthesized by chemical manipulation of the amino functionality of the compounds described in Schemes 24–53.




The compounds of the present invention and the intermediates described above wherein the B group contains an oxidizable group can be oxidized, e.g., N to N-oxide.
Schemes 24–55 describe how to make the A—B moieties of the present invention and schemes 1–6 describe how to incorporate them to prepare compounds of formula Id or Ie of the present invention. Scheme 56 depicts the preparation of compounds of the present invention of formula Id (Z1=N, Z2=CH, T1=CO, T2=CH2, n=1) wherein A—B is a phenyl pyridone group.




Scheme 57 shows the preparation of compounds of the present invention of formula Id (Z1=N, Z2=CH, T1=CO, T2=CO, n=1) wherein A—B is a phenyl pyridone group.




Scheme 58 depicts the preparation of compounds of the present invention of formula Id (Z1=N, Z2=CH, T1=CO, T2=CH2, n=2) wherein A—B is a phenyl pyridone group.




One diastereomer of a compound of Formula Id or Ie may be more potent against fXa than the others. Thus, the diastereomers shown below are considered to be part of the present invention. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride (Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602–2605). A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand (for example, Andrew S. Thompson, et al, Tetrahedron Lett. 1995, 36, 8937–8940).




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, 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 a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. The term 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
5-chloro-N{[1-(2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)phenyl)-5-oxopyrrolidin-3-yl]methyl}thiophene-2-carboxamide




Step A: A mixture of itaconic acid (130 mg, 1.0 mmol) and 2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)aniline, hydrochloride salt (317 mg, 1.0 mmol, WO 02/102380) were stirred at reflux in toluene for 18 hrs. The mixture was cooled to room temperature. Solvent was evaporated, and the residue was re-dissolved in ethyl acetate. The mixture was washed with water, brine and dried over MgSO4. HPLC purification (30% to 100% acetonitrile/water gradient) gave the desired product 1-(2-fluoro-4-(2-N,N-dimethylamino-methylphenyl)phenyl-5-oxopyrrolidine-3-carboxylic acid as white solid. LC-MS found: (M+1)+=357.3.
Step B: To a solution of the product obtained above (356 mg, 1.0 mmol) in THF was added BH3 in THF (5.0 mL, 1 M solution) at 0° C. under N2. After addition, the mixture was brought to room temperature and stirred for 8 hrs. The mixture was quenched with water and most of the THF was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, brine, and dried over MgSO4. HPLC purification (20% to 100% acetonitrile/water gradient) provided the desired product 1-[2-fluoro-4-(2-N,N-dimethylaminomethyl-phenyl)phenyl-4-(hydroxymethyl)pyrrolidin-2-one as white solid. LC-MS found: (M+1)+=343.2.
Step C: At 0° C. under N2, TEA was added to a mixture of the product obtained above (342 mg, 1.0 mmol) and MsCl (1.2 mmol) in dichloromethane. After addition, the resulted mixture was brought to room temperature and stirred for 2 hrs. The mixture was diluted with dichloromethane, washed with water, and dried over MgSO4. Prep TLC purification (5 MeOH/CHCl3) provided the desired product {1-[2-fluoro-4-(2-N,N-dimethylaminomethyl-phenyl)phenyl]-5-oxopyrrolidin-3-yl}methyl methanesulfonate as light yellow solid. LC-MS found: (M+1)+=421.4.
Step D: To a solution of the product obtained above (210 mg, 0.5 mmol) in DMF was added sodium azide (65 mg, 1.0 mmol). The mixture was stirred at 80° C. under N2 for 3 hrs. The mixture was cooled to room temperature and most of the DMF was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over MgSO4. Removal of solvent yielded the desired azide derivative which was dissolved in methanol, and the flask was purged with nitrogen gas. Then, Pd/C (cat.) was added. The mixture was hydrogenated under 1 atm for 2 hrs. The mixture was filtered through a pad of celite. HPLC purification (10% to 100% acetonitrile/water gradient) provided the desired amine as white solid. LC-Ms found: (M+1)+=342.4.
Step E: At 0° C. under N2, DIEA (diethyl-propyl-ethyl-amine) was added to a mixture of the product obtained above (34.1 mg, 0.1 mmol), 5-chlorothiophene-2-carboxylic acid (20.0 mg, 0.12 mmol), EDCI (23.0 mg, 0.12 mmol), and HOBt (16.2 mg, 0.12 mmol) in DMF (5 ml). After addition, the mixture was brought to room temperature and stirred for 3 hrs. The mixture was diluted with ethyl acetate; washed with water, 1N HCl, Sat. NaHCO3, and brine; and, dried over MgSO4. HPLC purification (30% to 100% acetonitrile/water gradient) provided the desired 5-chloro-N{[1-(2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)phenyl)-5-oxopyrrolidin-3-yl]methyl}thiophene-2-carboxamide as a white solid. LC-Ms found: (M+1)+=486.3.
Example 2
5-chloro-N-((1-(2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-sulfonamide




At 0° C. under N2, DIEA was added to a mixture of the product obtained from Step d in Example 1 (34.1 mg, 0.1 mmol) and 5-chlorothiophene-2-sulfonyl chloride (26.0 mg, 0.12 mmol) in dichloromethane. The mixture was stirred at 0° C. for 30 min. and at room temperature for 2 hrs. The mixture was diluted with dichloromethane, washed with water and brine, and dried over MgSO4. HPLC purification (30% to 100% acetonitrile/water gradient) provided the desired 5-chloro-N-((1-(2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-sulfonamide as white solid. LC-Ms found: (M+1)+=522.2.
Example 3
5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide




Part A. Hydrogen chloride gas was bubbled into a stirred suspension of trans-3-hydroxy-L-proline (25 g, 190 mmol) in MeOH (250 mL) at 0° C. for 10 min. The resulting clear solution was capped and stirred at room temperature for 6 h. It was concentrated under reduced pressure. The resulting white solids were triturated with either, filtered, and dried under vacuum to give (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride salt (32.5 g, yield: 93.7%).
Part B. To a suspension of the product from Part A (15.0 g, 82.4 mmol) in CH2Cl2 (500 mL) was added Et3N (22.7 mL, 164.8 mmol) at 0° C. under N2, followed by portionwise addition of di-tert-butyldicarbonate (17.6 g, 80.8 mmol). The resulting mixture was stirred at room temperature for overnight. It was partitioned between CH2Cl2 and H2O. The organic layer was washed with H2O (2×), 20% aqueous citric acid (1×), H2O, and brine; dried over Na2SO4; and concentrated to dryness to give an oil residue. The crude product was purified by FCC (silica gel) with 0–50% EtOAc/Hexanes to afford (2S,3S)-N-tert-butyloxycarbonyl-3-hydroxy-2-pyrrolidinecarboxylic acid methyl ester (16.4 g, yield: 81.1%) as a colorless oil.
Part C. To a solution of the product from Part B (5.0 g, 20.4 mmol) in CH2Cl2 (100 mL) at room temperature under N2, was added imidazole (2.78 g, 40.8 mmol), followed by the addition of tert-butyldimethylsilyl chloride (3.43 g, 22.6 mmol). After stirring at room temperature overnight, the reaction mixture as partitioned between CH2Cl2 and H2O. The organic layer was washed with 1N H3PO4, sat'd NaHCO3, and then brine; dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by FCC (silica gel) with 0–50% EtOAc/Hexanes as the solvents to give (2S,3S)-3-(tert-butyldimethylsilanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (6.6 g, yield: 90.1%). LC/MS (ESI): 360 (M+H).
Part D. To the stirred solution of the product from Part C (5.0 g, 13.92 mmol) in THF (50 mL) was added dropwise super-hydride (1.0 M THF solution, 70 mL, 70 mmol) at −78° C. under N2 during a 40-min period. The resulting mixture was warmed slowly to room temperature and stirred for 3 h. It was poured into crushed ice and stirred for 15 min. It was then extracted with EtOAc (2×); washed with sat'd NaHCO3 and brine; dried over MgSO4; filtered; and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc gradients) to give pure (2R,3S)-3-(tert-butyldimethylsilanyloxy)-2-hydroxymethylpyrroline-1-carboxylic acid tert-butyl ester (4.37 g, yield: 91%).
Part E. The product from Part D (4.37 g, 13.9 mmol) was stirred in dry CH2CH2 (100 ML) at 0° C. under N2. Dess-Martin Periodinane (8.8 g) was added as several portions. The resulting mixture was stirred at room temperature for 4 h. TLC showed completion of the reaction. Sat'd Na2S2O3 (15 ML) was added, followed by the addition of Sat'd NaHCO3 (15 mL). The organic layer was separated and washed with sat'd Na2S2O3, sat'd NaHCO3, brine, and H2O, sequentially. It was then dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel filtration (hexanes:EtOAc=1:0 to 10:1) to give pure (2S,3S)-3-(tert-butyldimethylsilanyloxy)-2-formylpyrroline-1-carboxylic acid tert-butyl ester (3.57 g, 75%) as colorless oil.
Part F. The product from Part E (640 mg, 1.95 mmol) was stirred in 1,2-dichloroethane (6 mL) at room temperature under N2. The aniline (450 mg, 2.42 mmol) was added, followed by the addition of NaBH(OAc)3 (2.1 g, 10 mmol) and HOAc (0.1 mL). The resulting mixture was stirred at room temperature for 1 h, LCMS showed completion of the reaction. Sat'd NaHCO3 was the added. It was extracted with EtOAc; washed with H2O and brine; dried over MgSO4; filtered; and concentrated to dryness. The residue was purified by FCC (silica gel, hexanes:EtOAc=1:0 to 1:1) to give pure (2R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-2-{[4-(2-oxo-2H-pyridin-1-yl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (650 mg, yield: 67%). LC/MS (ESI) 500.30 (M+H), 444.30 (M−tBu+H), 400.30 (M−Boc+H), tR=4.11 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run).
Part G. The product from Part F (550 mg, 1.1 mmol) was stirred in CH2Cl2 (10 mL) and TFA (4 mL) at room temperature for 1 h. It was evaporated; dissolved in CH2Cl2; washed with sat'd NaHCO3 and H2O; dried over MgSO4; filtered; and concentrated to dryness to give crude 1-(4-{[(2R,3S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-ylmethyl]-amino}-phenyl)-1H-pyridin-2-one. LC/MS (ESI) 400.30 (M+H), tR=3.11 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run). This product was dissolved in CH2Cl2 (10 mL) and stirred at 0° C. under N2. DIEA (1.02 mL) was added, followed by dropwise addition of phosgene (20% in toluene, 0.5 mL). The resulting mixture was warmed to r.t. and stirred for 2 h. It was evaporated and purified by FCC (hexanes:EtOAc+1:1 to 0:1) to give pure (7S,7aR)-7-(tert-butyl-dimethyl-silanyloxy)-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (400 mg, 85.6%). LC/MS (ESI) 426.24 (M+H), tR=3.86 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run).
Part H. The product from Part G (390 mg, 0.92 mmol) was stirred in THF (6 mL) at 0° C. under N2. TBAF (1.0 M in THF, 1.5 mL, 1.5 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. TLC showed completion of the reaction. EtOAc was added. The mixture was washed with sat'd NH4Cl, H2O, and brine; dried over MgSO4; filtered; and concentrated to dryness. The residue was purified by FCC (hexanes:EtOAc=1:1 to 0:1) to give (7S,7aR)-7-hydroxy-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (200 mg, yield: 70%). LC-MS (ESI) 312.18 (M+H), tR=1.66 min (10–90% MeOH in H2O with 0.1% TFA in a 4-min run).
Part I. The product from Part H (200 mg, 0.64 mmol) was stirred in dry CH2Cl2 (6 mL) at 0° C. under N2. Et3N (1.7 mL) was added followed by the addition of MsCl (0.9 mL). The solution was stirred at 0° C. for 45 min. TLC showed completion of the reaction. It was washed with H2O and brine; dried over Na2SO4; filtered; and concentrated to dryness. The residue was dissolved in DMSO (1 mL), and NaN3 (200 mg) was added. The resulting mixture was heated at 80° C. for 24 h. It was cooled, partitioned between EtOAc and H2O, washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by FCC (silica gel, EtOAc) to give (7R,7aR)-7-azido-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (156 mg, yield: 72%).
Part J. The product from Part I (230 mg, 0.68 mmol) was stirred in THF (4 mL). PPh3 (250 mg, 0.95 mmol) was added, followed by the addition of H2O (0.1 mL). The resulting mixture was heated at 50–70° C. for 2 days. After cooling, it was evaporated to dryness to give crude (7R,7aR)-7-amino-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one which was used directly in the next step. LC/MS (ESI) 311.21 (M+H), tR=1.29 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run).
Part K. One quarter of the crude product of Part J (ca. 50 mg) was dissolved in DMF (0.5 mL). 5-Chlorothiophene carboxylic acid (15 mg) was added followed by the addition of NMM (0.02 mL) and BOP (35 mg). The resulting mixture was stirred at room temperature for 1 h. It was purified by reverse phase HPLC to give the desired title compound: LC/MS (ESI) 455.17, 457.18 (M+H), tR=2.74 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run).
Using a procedure similar to that of Example 3, the following Examples 4–6 were prepared.
Example 4
6-Chloro-naphthalene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide




LC/MS (ESI) 500.14, 502.18 (M+H), tR=2.79 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run).
Example 5
3-Chloro-1H-indole-6-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide




MS (ESI) 488.2 (M+H).
Example 6
4-Chloro-N-{(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-benzamide




LC/MS (ESI): 449.18, 551.20 (M+H), tR=2.67 min (10–90% MeOH in H2O with 0.1% TFA in a 4 min run).
The following tables list representative compounds of the present invention that can be prepared by the methods of the above examples as well as by methods known to those of skill in the art.
TABLE 1


    1. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    2. 4-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    3. 4-methoxy-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    4. 4-fluoro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    5. 3-carbamimidoyl-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    6. 3-(carbamimidoyl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    7. 3-(benzamide)-4-fluoro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    8. 3-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    9. 3-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    10. 4-fluoro-N1-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isophthalamide
    11. 4-chloro-N1-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isophthalamide
    12. 3-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    13. 5-chloro-N1-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)phthalamide
    14. 5-fluoro-N1-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)phthalamide
    15. 5-methoxy-N1-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)phthalamide
    16. 4-ethyl-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    17. 4-(aminomethyl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    18. N1,N1-dimethyl-N3-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isophthalamide
    19. 3-chloro-4-fluoro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    20. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)nicotinamide
    21. 6-methoxy-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)nicotinamide
    22. 6-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)nicotinamide
    23. 2-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isonicotinamide
    24. 2-methoxy-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isonicotinamide
    25. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    26. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    27. 2-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    28. 3-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-7-carboxamide
    29. 3-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    30. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-2-carboxamide
    31. 7-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-3-carboxamide
    32. 7-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    33. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    34. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-6-carboxamide
    35. 1-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-6-carboxamide
    36. 3-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-6-carboxamide
    37. 2-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    38. 1-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-6-carboxamide
    39. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    40. 6-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    41. 2-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    42. 3-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-7-carboxamide
    43. 6-methoxy-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    44. 2-methoxy-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    45. 6-cyano-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    46. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    47. 7-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    48. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    49. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    50. 4-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    51. 4,6-dichloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    52. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    53. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    54. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    55. 5-chloro-6-fluoro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    56. 4-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    57. 7-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    58. 3,6-dichloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    59. 6-bromo-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    60. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide
    61. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thieno[3,2-c]pyridine-2-carboxamide
    62. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thieno[3,2-b]pyridine-2-carboxamide
    63. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    64. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]oxazole-2-carboxamide
    65. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]oxazole-2-carboxamide
    66. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazole-2-carboxamide
    67. 6-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    68. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    69. 7-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    70. 7-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    71. 6-amino-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    72. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-5-carboxamide
    73. 3-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-5-carboxamide
    74. 3-cyano-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-5-carboxamide
    75. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    76. 3-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    77. 3-bromo-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    78. 2-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-6-carboxamide
    79. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)furan-2-carboxamide
    80. 5-chloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    81. 3,5-dichloro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    82. 5-chloro-3-fluoro-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    83. 5-bromo-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    84. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-5-phenylthiophene-2-carboxamide
    85. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-5-(pyridin-2-yl)thiophene-2-carboxamide
    86. 5-(6-chloropyridin-2-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    87. 5-cyano-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    88. 5-(5-chlorothiophen-2-yl)-N-((5-oxo-1-(4-(2-oxopiperidin 1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    89. 5-(isothiazol-5-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    90. 5-(3-chloroisothiazol-5-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    91. 5-(3-chloroisoxazol-5-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    92. 5-(3-methylisoxazol-5-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    93. 5-(5-methyl-2H-1,2,4-triazol-3-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    94. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)-5-(1H-tetrazol-5-yl)thiophene-2-carboxamide
    95. (E)-3-(4-chlorophenyl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)acrylamide
    96. 3-(4-chlorophenyl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)propanamide
    97. (E)-3-(5-chlorothiophen-2-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)acrylamide
    98. 3-(5-chlorothiophen-2-yl)-N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)propanamide
    99. N-((5-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)pyrrolidin-3-yl)methyl)cyclohexanecarboxamide
    100. N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    101. 4-chloro-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    102. N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    103. 3-carbamimidoyl-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    104. 3-carbamimidoyl-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    105. 3-amino-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    106. 3-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    107. N1-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)isophthalamide
    108. 3-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    109. 3-(aminomethyl)-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    110. 3-((dimethylamino)methyl)-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    111. 4-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    112. 4-methoxy-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    113. 6-methoxy-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)nicotinamide
    114. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)nicotinamide
    115. 6-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)nicotinamide
    116. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    117. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    118. 7-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    119. 2-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    120. 2-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    121. 7-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    122. 6-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    123. 2-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    124. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    125. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)isoquinoline-6-carboxamide
    126. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrobenzofuran-2-carboxamide
    127. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrobenzofuran-2-carboxamide
    128. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydro-1H-indole-2-carboxamide
    129. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrobenzo[b]thiophene-2-carboxamide
    130. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrobenzo[b]thiophene-2-carboxamide
    131. 5-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrobenzo[b]thiophene-2-carboxamide
    132. 5-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrothieno[3,2-b]pyridine-2-carboxamide
    133. 5-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrothieno[3,2-b]pyridine-2-carboxamide
    134. 5-amino-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrothieno[2,3-b]pyridine-2-carboxamide
    135. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2,7a-dihydrothieno[2,3-b]pyridine-2-carboxamide
    136. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    137. 3-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    138. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3H-benzo[d]imidazole-5-carboxamide
    139. 2-methyl-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3H-benzo[d]imidazole-5-carboxamide
    140. 2-methyl-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]oxazole-6-carboxamide
    141. 6-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]oxazole-2-carboxamide
    142. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]oxazole-2-carboxamide
    143. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazole-2-carboxamide
    144. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    145. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    146. 5-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    147. 5-chloro-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)furan-2-carboxamide
    148. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-phenylthiophene-2-carboxamide
    149. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-(pyridin-2-yl)thiophene-2-carboxamide
    150. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-(thiophen-2-yl)thiophene-2-carboxamide
    151. 5-(5-chlorothiophen-2-yl)-N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    152. N-((1-(4-(N-methyl-2-(pyrrolidin-1-yl)acetamido)phenyl)-5-oxopyrrolidin-3-yl)methyl)cyclohexanecarboxamide
    153. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)cyclohexanecarboxamide
    154. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    155. 4-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    156. 4-methoxy-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    157. 4-cyano-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    158. 4-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    159. 4-(aminomethyl)-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    160. 3-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    161. 3-(aminomethyl)-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    162. N1-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)isophthalamide
    163. 2-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)isonicotinamide
    164. 2-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)isonicotinamide
    165. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    166. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    167. 2-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    168. 7-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    169. 7-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    170. 2-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)quinoline-7-carboxamide
    171. 6-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    172. 6-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    173. 3-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)isoquinoline-7-carboxamide
    174. 6-amino-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)furo[3,2-c]pyridine-2-carboxamide
    175. 6-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)furo[3,2-c]pyridine-2-carboxamide
    176. 6-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    177. 6-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    178. 6-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    179. 6-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazole-2-carboxamide
    180. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-benzo[d]imidazole-2-carboxamide
    181. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    182. 5-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    183. 5-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    184. 5-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    185. 5-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    186. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    187. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    188. 5-chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    189. 5-methyl-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    190. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-5-phenylthiophene-2-carboxamide
    191. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-5-(pyridin-2-yl)thiophene-2-carboxamide
    192. N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)-5-(thiophen-2-yl)thiophene-2-carboxamide
    193. 5-(5-chlorothiophen-2-yl)-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    194. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    195. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    196. 4-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    197. 3-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    198. 3-(aminomethyl)-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    199. 3-((dimethylamino)methyl)-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    200. 3-carbamimidoyl-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    201. 3-amino-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    202. 3-amino-N-((1-(4-(2-((methylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    203. 3-amino-N-((1-(2-fluoro-4-(2-((methylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    204. 3-amino-N-((1-(3-fluoro-4-(2-((methylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    205. 3-amino-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-3-fluorophenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    206. 3-amino-N-((1-(5-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)pyridin-2-yl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    207. 3-amino-N-((1-(6-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)pyridin-3-yl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    208. 3-amino-N-((1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    209. N1-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)isophthalamide
    210. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    211. 7-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    212. 6-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    213. 2-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    214. 2-amino-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    215. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-methylquinoline-6-carboxamide
    216. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-methylfuro[3,2-b]pyridine-2-carboxamide
    217. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)furo[3,2-b]pyridine-2-carboxamide
    218. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thieno[3,2-b]pyridine-2-carboxamide
    219. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    220. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-methylbenzo[b]thiophene-2-carboxamide
    221. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    222. 6-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    223. 6-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide
    224. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-6-methylthieno[2,3-b]pyridine-2-carboxamide
    225. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-6-methylbenzo[b]thiophene-2-carboxamide
    226. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-6-methyl-1H-indole-2-carboxamide
    227. 6-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    228. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    229. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-methyl-i H-indole-2-carboxamide
    230. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    231. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-benzo[d]imidazole-2-carboxamide
    232. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]oxazole-2-carboxamide
    233. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    234. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-methylbenzo[d]thiazole-2-carboxamide
    235. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    236. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]oxazole-2-carboxamide
    237. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-methylthiophene-2-carboxamide
    238. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    239. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)furan-2-carboxamide
    240. N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-(thiophen-2-yl)thiophene-2-carboxamide
    241. 5-(5-chlorothiophen-2-yl)-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    242. 5-chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    243. 5-chloro-N-((1-(5-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)pyridin-2-yl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    244. 5-chloro-N-((1-(6-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)pyridin-3-yl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    245. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    246. 5-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    247. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    248. 5-(5-chlorothiophen-2-yl)-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    249. N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-(thiophen-2-yl)thiophene-2-carboxamide
    250. 5-(5-chlorothiophen-2-yl)-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    251. N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    252. N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    253. 6-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    254. 6-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    255. 6-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide
    256. 6-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide
    257. N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    258. N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    259. 6-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    260. 6-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    261. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    262. 5-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    263. 5-chloro-N-((5-oxo-1-(4-(1-(piperidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    264. 5-chloro-N-((1-(4-(1-(morpholinomethyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    265. 5-chloro-N-((1-(4-(1-(morpholinomethyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide
    266. 5-chloro-N-((5-oxo-1-(4-(1-(piperidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide
    267. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide
    268. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thieno[3,2-b]pyridine-2-carboxamide
    269. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiazolo[4,5-b]pyridine-2-carboxamide
    270. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    271. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    272. 5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    273. 6-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    274. 6-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)quinoline-2-carboxamide
    275. 6-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)quinoline-2-carboxamide
    276. 2-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    277. 2-amino-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)quinoline-6-carboxamide
    278. N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    279. 7-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-2-naphthamide
    280. 7-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    281. N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-5-carboxamide
    282. 3-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-5-carboxamide
    283. 3-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)-1H-indole-5-carboxamide
    284. 4-amino-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    285. 4-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    286. 4-chloro-N-((1-(4-(1-((diethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    287. N-((1-(4-(1-((diethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    288. N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    289. 3-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    290. 3-chloro-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)benzamide
    291. 3-amino-N-((5-oxo-1-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    292. 3-amino-N-((1-(4-(1-((diethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    293. 3-amino-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    294. 3-amino-N-((1-(4-(1-((methylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    295. 3-amino-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]isoxazole-5-carboxamide
    296. 3-carbamimidoyl-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-hydroxybenzamide
    297. 3-carbamimidoyl-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    298. 3-carbamimidoyl-N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    299. 3-carbamimidoyl-N-((1-(4-(2-methyl-1-(piperidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    300. 3-carbamimidoyl-N-((1-(4-(2-methyl-1-morpholinopropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    301. N1-((1-(4-(2-methyl-1-morpholinopropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)isophthalamide
    302. 3-(aminomethyl)-N-((1-(4-(2-methyl-1-morpholinopropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    303. 3-chloro-N-((1-(4-(2-methyl-1-morpholinopropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    304. 4-methoxy-N-((1-(4-(2-methyl-1-morpholinopropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    305. 4-methoxy-N-((1-(4-(2-methyl-1-(piperidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    306. N-((1-(4-(1-(diethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    307. N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    308. N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzamide
    309. N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    310. 7-chloro-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    311. N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    312. 6-chloro-N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    313. 6-chloro-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-2-naphthamide
    314. 3-chloro-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    315. 3-chloro-N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-6-carboxamide
    316. (E)-N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3-(thiophen-2-yl)acrylamide
    317. (E)-3-(5-chlorothiophen-2-yl)-N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)acrylamide
    318. N-((1-(4-(2-methyl 1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzofuran-2-carboxamide
    319. N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    320. N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    321. N-((1-(4-(1-(diethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    322. 6-chloro-N-((1-(4-(1-(diethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    323. 5-chloro-N-((1-(4-(1-(diethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    324. 5-chloro-N-((1-(4-(1-(diethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[d]thiazole-2-carboxamide
    325. 5-chloro-N-((1-(4-(1-(diethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    326. 5-chloro-N-((1-(4-(1-(dimethylamino)-2-methylpropan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    327. 5-chloro-N-((1-(4-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide
    328. N-((1-(4-carbamimidoylphenyl)-5-oxopyrrolidin-3-yl)methyl)-5-chlorothiophene-2-carboxamide
    329. (Z)—N-((1-(4-(N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-chlorothiophene-2-carboxamide
    330. (Z)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-5-chlorothiophene-2-carboxamide
    331. (Z)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)benzo[b]thiophene-2-carboxamide
    332. (Z)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-6-chlorobenzo[b]thiophene-2-carboxamide
    333. (Z)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-1H-indole-2-carboxamide
    334. (Z)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-6-chloro-1H-indole-2-carboxamide
    335. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-6-chloro-1H-indole-2-carboxamide
    336. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-7-chloro-2-naphthamide
    337. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-chlorobenzamide
    338. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-4-methoxybenzamide
    339. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3-chlorobenzamide
    340. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3-aminobenzo[d]isoxazole-5-carboxamide
    341. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3-carbamimidoyl-4-hydroxybenzamide
    342. (E)—N-((1-(4-(N,N-dimethyl-N′-(methylsulfonyl)carbamimidoyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)-3-carbamimidoylbenzamide


TABLE 2


    1. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    2. 6-Chloro-naphthalene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    3. 3-Chloro-1H-indole-6-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    4. 4-Chloro-N-{(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-benzamide
    5. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    6. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    7. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(3-oxo-morpholin-4-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol7-yl}-amide
    8. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(3-oxo-2-aza-bicyclo[2.2.1]hept-2-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    9. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-[1,3]oxoazinan-3-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    10. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    11. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    12. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(3-oxo-2-aza-bicyclo[2.2.1]hept-2-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    13. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(3-oxo-morpholin-4-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    14. 5-Chloro-thiophene-2-carboxylic acid {(3aR,4R)-1,1-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    15. 5-Chloro-thiophene-2-carboxylic acid {(3aR,4R)-1,1-dioxo-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    16. 5-Chloro-thiophene-2-carboxylic acid {(3aR,4R)-1,1-dioxo-2-[4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    17. 5-Chloro-thiophene-2-carboxylic acid {(3aR,4R)-1,1-dioxo-2-[4-(3-oxo-morpholin-4-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    18. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    19. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1-oxo-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    20. 5-Chloro-thiophene-2-carboxylic acid {(3 aS,4R)-1,1,3-trioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    21. 3-Chloro-1H-indole-6-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    22. 3-Chloro-1H-indole-6-carboxylic acid {(7R,7aS)-1-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    23. 3-Chloro-1H-indole-6-carboxylic acid {(7R,7aS)-1-oxo-2-[4-(3-oxo-morpholin-4-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    24. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4R)-1,1-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    25. 5-Chloro-1H-indole-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    26. 5-Chloro-1H-indole-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    27. 5-Chloro-1H-indole-2-carboxylic acid {(3aR,4R)-1,1-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-hexahydro-1λ6-thia-2,6a-diaza-pentalen-4-yl}-amide
    28. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    29. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(3-oxo-morpholin-4-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    30. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aS)-1,3-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    31. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    32. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aS)-1,3-dioxo-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    33. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aS)-1,3-dioxo-2-[4-(3-oxo-2-aza-bicyclo[2.2.1]hept-2-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    34. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    35. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aS)-1-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    36. 5-Chloro-1H-indole-2-carboxylic acid {(3aR,4S)-1,1-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    37. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-1-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    38. 5-Chloro-1H-indole-2-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    39. 5-Chloro-1H-indole-2-carboxylic acid {(8R,8aS)-1,3-dioxo-2-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    40. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[(2-dimethylamino-acetyl)-methyl-amino]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    41. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[(2-diethylamino-acetyl)-methyl-amino]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    42. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[methyl-(2-piperidin-1-yl-acetyl)-amino]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    43. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[methyl-(2-pyrrolidin-1-yl-acetyl)-amino]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    44. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[(2-dimethylamino-acetyl)-methyl-amino]-phenyl}-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    45. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[methyl-(2-pyrrolidin-1-yl-acetyl)-amino]-phenyl}-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    46. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aR)-2-{4-[(2-dimethylamino-acetyl)-methyl-amino]-phenyl}-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    47. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aR)-2-{4-[methyl-(2-pyrrolidin-1-yl-acetyl)-amino]-phenyl}-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    48. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[(2-dimethylamino-acetyl)-methyl-amino]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    49. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[methyl-(2-pyrrolidin-1-yl-acetyl)-amino]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    50. 3-Chloro-1H-indole-6-carboxylic acid ((3aR,4S)-2-{4-[(2-dimethylamino-acetyl)-methyl-amino]-phenyl}-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    51. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(1-isopropyl-piperidin-4-yl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    52. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(1-cyclopropyl-piperidin-4-yl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    53. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(1-cyclohexyl-piperidin-4-yl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    54. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(1′-methyl-[1,4′]bipiperidinyl-4-yl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    55. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aS)-2-(1-isopropyl-piperidin-4-yl)-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    56. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aS)-2-(1-isopropyl-piperidin-4-yl)-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    57. 3-Chloro-1H-indole-6-carboxylic acid [(3aR,4S)-2-(1-isopropyl-piperidin-4-yl)-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl]-amide
    58. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(2′-methanesulfonyl-biphenyl-4-yl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    59. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-3-oxo-2-(2′-sulfamoyl-biphenyl-4-yl)-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    60. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(2′-dimethylaminomethyl-biphenyl-4-yl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    61. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-dimethylamino-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    62. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(4-methyl-[1,4]diazepan-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    63. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-morpholin-4-yl-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    64. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-dimethylcarbamoyl-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    65. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(pyrrolidine-1-carbonyl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    66. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aR)-2-(2′-methanesulfonyl-biphenyl-4-yl)-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    67. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aR)-3-oxo-2-(2′-sulfamoyl-biphenyl-4-yl)-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    68. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aR)-2-(2′-dimethylaminomethyl-biphenyl-4-yl)-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    69. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(4-methyl-[1,4]diazepan-1-yl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]imidazol-8-yl}-amide
    70. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    71. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aS)-2-(4-{[methanesulfonylimino]-pyrrolidin-1-yl-methyl}-phenyl)-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    72. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(imino-pyrrolidin-1-yl-methyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    73. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    74. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    75. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-methyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    76. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-ethyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    77. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-phenyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    78. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    79. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-acetylamino-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    80. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-methanesulfonylamino-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    81. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-methoxy-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    82. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-{dimethylamino-[methanesulfonylimino]-methyl}-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    83. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-{[methanesulfonylimino]-pyrrolidin-1-yl-methyl}-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    84. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(imino-pyrrolidin-1-yl-methyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    85. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(N,N-dimethyl-carbamimidoyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    86. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4(N′-methoxy-N,N-dimethyl-carbamimidoyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    87. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    88. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(N′-methoxy-N,N-dimethyl-carbamimidoyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    89. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aR)-2-(4-{dimethylamino-[methanesulfonylimino]-phenyl)-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    90. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aR)-2-(4-{[methanesulfonylimino]-pyrrolidin-1-yl-methyl}-phenyl)-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    91. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(imino-pyrrolidin-1-yl-methyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    92. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(N,N-dimethyl-carbamimidoyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    93. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    94. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(N′-methoxy-N,N-dimethyl-carbamimidoyl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    95. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(N,N-dimethyl-carbamimidoyl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    96. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aS)-2-(4-{[methanesulfonylimino]-pyrrolidin-1-yl-methyl}-phenyl)-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    97. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4R)-2-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    98. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4S)-2-[4-(N,N-dimethyl-carbamimidoyl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    99. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    100. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(2-pyrrolidin-1-ylmethyl-imidazol-1-yl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    101. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-{2-[(methanesulfonyl-methyl-amino)-methyl]-imidazol-1-yl}-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    102. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-{2-[(acetyl-methyl-amino)-methyl]-imidazol-1-yl}-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    103. [1-(4-{(7R,7aR)-7-[(5-Chloro-thiophene-2-carbonyl)-amino]-3-oxo-tetrahydro-pyrrolo[1,2-c]imidazol-2-yl}-phenyl)-1H-imidazol-2-ylmethyl]-methyl-carbamic acid methyl ester
    104. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[2-(isopropylamino-methyl)-imidazol-1-yl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    105. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    106. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    107. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aS)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    108. 3-Chloro-1H-indole-6-carboxylic acid {(3aS,4R)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-1,1,3-trioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    109. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4R)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    110. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    111. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(2-dimethylaminomethyl-imidazol-1-yl)-phenyl]-1-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    112. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    113. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-morpholin-4-ylmethyl-cyclobutyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    114. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-{1-[(5-methyl-thiazol-2-ylamino)-methyl]-cyclobutyl}-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    115. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-3-oxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclobutyl]-phenyl}-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    116. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclobutyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    117. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopentyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    118. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-3-oxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclopropyl]-phenyl}-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    119. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclopropyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    120. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1,1-dimethyl-3-morpholin-4-yl-propyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    121. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-methoxymethyl-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    122. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-methoxymethyl-cyclobutyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    123. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-1-oxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclobutyl]-phenyl}-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    124. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-morpholin-4-ylmethyl-cyclobutyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    125. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclobutyl]-phenyl}-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    126. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopentyl]-phenyl}-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    127. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-1-oxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclopropyl]-phenyl}-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    128. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclopropyl]-phenyl}-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    129. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    130. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1,1-dimethyl-3-morpholin-4-yl-propyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    131. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-methoxymethyl-cyclopropyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    132. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-methoxymethyl-cyclobutyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    133. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    134. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-morpholin-4-ylmethyl-cyclobutyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    135. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aS)-2-(4-{1-[(5-methyl-thiazol-2-ylamino)-methyl]-cyclobutyl}-phenyl)-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    136. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-1,3-dioxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclobutyl]-phenyl}-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    137. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclobutyl]-phenyl}-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    138. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopentyl]-phenyl}-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    139. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-1,3-dioxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclopropyl]-phenyl}-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    140. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclopropyl]-phenyl}-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    141. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-methoxymethyl-cyclopropyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    142. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1,1-dimethyl-3-morpholin-4-yl-propyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    143. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-dimethylamino-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    144. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    145. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    146. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-carbamoylmethyl-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    147. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-dimethylamino-cyclobutyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    148. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-dimethylaminomethyl-cyclobutyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    149. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(2-dimethylamino-ethyl)-cyclobutyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    150. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-carbamoylmethyl-cyclobutyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    151. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-dimethylamino-cyclopentyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    152. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-dimethylaminomethyl-cyclopentyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    153. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopentyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    154. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-carbamoylmethyl-cyclopentyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    155. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-dimethylamino-1,1-dimethyl-ethyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    156. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(3-dimethylamino-1,1-dimethyl-propyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    157. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(2-carbamoyl-1,1-dimethyl-ethyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    158. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-methanesulfonyl-1-methyl-ethyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    159. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-methanesulfonyl-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    160. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-methanesulfonylmethyl-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    161. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-3-oxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    162. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aR)-2-{4-[1-(3-hydroxy-pyrrolidin-1-ylmethyl)-cyclopropyl]-phenyl}-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    163. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aR)-2-[4-(1-morpholin-4-ylmethyl-cyclopropyl)-phenyl]-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    164. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aR)-2-(4-{1-[(5-methyl-thiazol-2-ylamino)-methyl]-cyclopropyl}-phenyl)-3-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    165. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-dimethylamino-cyclopropyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    166. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    167. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    168. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-carbamoylmethyl-cyclopropyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    169. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-dimethylamino-cyclobutyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    170. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-dimethylaminomethyl-cyclobutyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    171. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclobutyl]-phenyl}-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    172. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-carbamoylmethyl-cyclobutyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    173. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(2-dimethylamino-1,1-dimethyl-ethyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    174. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1-oxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    175. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-morpholin-4-ylmethyl-cyclopropyl)-phenyl]-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    176. 5-Chloro-thiophene-2-carboxylic acid [(7R,7aS)-2-(4-{1-[(5-methyl-thiazol-2-ylamino)-methyl]-cyclopropyl}-phenyl)-1-oxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl]-amide
    177. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4S)-1,1-dioxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-phenyl]-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    178. 3-Chloro-1H-indole-6-carboxylic acid ((3aR,4R)-1,1-dioxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclobutyl]-phenyl}-octahydro-1λ6-1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    179. 3-Chloro-1H-indole-6-carboxylic acid ((3aR,4R)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclobutyl]-phenyl}-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    180. 3-Chloro-1H-indole-6-carboxylic acid ((3aR,4R)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopentyl]-phenyl}-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    181. 3-Chloro-1H-indole-6-carboxylic acid ((3 aR,4R)-1,1-dioxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclopropyl]-phenyl}-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    182. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4R)-2-[4-(1,1-dimethyl-3-morpholin-4-yl-propyl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    183. 3-Chloro-1H-indole-6-carboxylic acid ((3aR,4R)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclopropyl]-phenyl}-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    184. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4S)-2-[4-(1-methoxymethyl-cyclopropyl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    185. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-1,3-dioxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclobutyl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    186. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aS)-2-(4-{1-[(5-methyl-thiazol-2-ylamino)-methyl]-cyclobutyl}-phenyl)-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    187. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-1,3-dioxo-2-{4-[1-(2-pyrrolidin-1-yl-ethyl)-cyclobutyl]-phenyl}-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    188. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(1-methoxymethyl-cyclopropyl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    189. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclobutyl]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    190. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopentyl]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    191. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    192. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(1,1-dimethyl-3-pyrrolidin-1-yl-propyl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    193. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclopropyl]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    194. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4S)-2-[4-(1-dimethylamino-cyclopropyl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    195. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4R)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    196. 3-Chloro-1H-indole-6-carboxylic acid ((3aR,4R)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl)-amide
    197. 3-Chloro-1H-indole-6-carboxylic acid {(3aR,4R)-2-[4-(1-carbamoylmethyl-cyclopropyl)-phenyl]-1,1-dioxo-octahydro-1λ6-[1,2,5]thiadiazolo[2,3-a]pyridin-4-yl}-amide
    198. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(1-dimethylamino-cyclopropyl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    199. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    200. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-1,3-dioxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    201. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aS)-1,3-dioxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    202. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(1-dimethylamino-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    203. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    204. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aR)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    205. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(1-carbamoylmethyl-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    206. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    207. 3-Chloro-1H-indole-6-carboxylic acid {(8S,8aR)-2-[4-(1-methanesulfonylmethyl-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    208. 3-Chloro-1H-indole-6-carboxylic acid [(8R,8aR)-2-(4-{1-[(5-methyl-thiazol-2-ylamino)-methyl]-cyclopropyl}-phenyl)-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl]-amide
    209. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(1-morpholin-4-ylmethyl-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    210. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-dimethylamino-cyclopropyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    211. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    212. 5-Chloro-thiophene-2-carboxylic acid ((7R,7aS)-2-{4-[1-(2-dimethylamino-ethyl)-cyclopropyl]-phenyl}-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl)-amide
    213. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-2-[4-(1-morpholin-4-ylmethyl-cyclopropyl)-phenyl]-1,3-dioxo-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    214. 5-Chloro-thiophene-2-carboxylic acid {(7R,7aS)-1,3-dioxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-7-yl}-amide
    215. 3-Chloro-1H-indole-6-carboxylic acid ((8R,8aR)-2-{4-[1-(2-morpholin-4-yl-ethyl)-cyclopropyl]-phenyl}-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl)-amide
    216. 3-Chloro-1H-indole-6-carboxylic acid {(8R,8aR)-2-[4-(1-methoxymethyl-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    217. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-2-[4-(1-dimethylaminomethyl-cyclopropyl)-phenyl]-3-oxo-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide
    218. 5-Chloro-thiophene-2-carboxylic acid {(8R,8aR)-3-oxo-2-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-octahydro-imidazo[1,5-a]pyridin-8-yl}-amide


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 formula I:




or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
G is thienyl substituted with 1–3 R;
R is selected from H, C1-4 alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, —CN, 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, C(═NR8)NR7R9, NHC(═NR8)NR7R9, ONHC(═NR8)NR7R9, NR8CH(═NR7), (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, provided that S(O)pR7 and S(O)2R3 form other than S(O)2H or S(O)H;
G1 is selected from (CR3R3a)uNR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)w, (CR3R3a)uNR3bC(O)O(CR3R3a)w, (CR3R3a)uNR3bC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(S)NR3b(CR3R3a)w, (CR3R3a)uNR3bS(O)2(CR3R3a)w, (CR3R3a)uNR3bS(O)2NR3b(CR3R3a)w, (CR3R3a)uNRR3e(CR3R3a)w, (CR3R3a)uNR3b(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(O)NR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)uC(S)NR3b(CR3R3a)w, and (CR3R3a)uNR3bC(S)(CR3R3a)uC(O)NR3b(CR3R3a)w, wherein u is 1 and w is selected from 0, 1, 2, and 3, and the right side of G1 is attached to ring G;
A is phenyl substituted with 0–2 R4 4;
B is Y;
Y is C3-10 carbocycle substituted 0–2 R4 and 0–1 R4a;
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;
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, and C3-6 carbocycle substituted with 0–2 R4b, 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, NR2R2aforms 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 R4cand 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, NR2dR2dforms 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 R4cand 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;
R3 at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)CH2, 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;
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, and —(C0-4 alkyl)—5–10 membered carbocycle substituted with 0–3 R1a;
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, CR3R3gforms a cyclopropyl group;
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, and (CR3R3a)r-5–6 membered carbocycle 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)rCN, (CR3R3g)rC(═NR2d)NR2dR2d, (CR3R3g)rNR2dC(═NR2d)NR2dR2d, (CR3R3g)rNR2dC(R2e)(═NR2d), (CR3R3g)rNR2dR2d, (CR3R3g)rN(→O)R2dR2d, (CR3R3g)rOR2d, (CR3R3g) —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)rNR2dC(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)NR2R 2a, (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;
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)r NR3SO2CF3, (CH2)rNR3SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (CH2)rS(O)pphenyl, (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)—, C14 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-C 1-4 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.

2. A compound according to claim 1, wherein:
G is thienyl substituted with 1–2 R;
R is selected from H, C1-4 alkyl, F, Cl, OH, OCH3, OCH2CH3, OCH(CH3)2, CN, C(═NH)NH2, 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, and OCF3; 
G1 is selected from (CR3R3a)uNR3b(CR3R3a)w, (CR3R3a)uNR3bC(O)(CR3R3a)w, (CR3R3a)uNR3bS(O)2(CR3R3a)w, and (CR3R3a)uNR3e(CR3R3a)w, wherein u is 1 and w is selected from 0, 1 and 2,and the right side of G1 is attached to ring G;
Y is selected from one of the following carbocycl that are substituted with 1 R4a and 0–2 R4: cyclopropyl, cyclopentyl, cyclohexyl, and phenyl
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 R1aforms other than an N-halo, N—S, O—O, or N—CN bond;
R1bis 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)pR 2, 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, and C5-6 carbocycle substituted with 0–2 R4b, provided that R1bforms 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 R4band consisting of: 0–1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
R2b, at each occurrence, is selected from CF3, C1-4 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 R4cand consisting of: carbon atoms and 1–4 heteroatoms selected from the group consisting of N, O, and S(O)p, provided that R2dforms 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, NR2dR2dforms a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0–2 R4band consisting of: 0–1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
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 R4cand 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;
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;
R3b, at each occurrence, is selected from H, CF3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, and —(C0-1 alkyl)—5–6 membered carbocycle substituted with 0–1 R1a;
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, and 5–6 membered carbocycle 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, NR3 C(O)NR3R3a, CH2NR3 C(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)NR 2R2a, (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; 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, NR3 C(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; and,
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.

3. A compound according to claim 2, wherein:
G is selected from:
Y is selected from one of the following carbocycles that are substituted with 1 R4aand 0–1 R4: cyclopentyl, cyclohexyl, and phenyl:
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;
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, and phenyl substituted with 0–2 R4b, provided that R1bforms 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)2b, enzyl 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 R4band consisting of: 0–1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
R2b, at each occurrence, is selected from CF3, C1-4 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 R4, 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 R4cand 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, R4, 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, C5–6 membered heterocycle substituted with 0–2 R4cand 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 R4cand 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)pmoiety;
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)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;
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.

4. A compound according to claim 3, wherein:
G1 is selected from CH2NR3bCH2, CH2NR3bC(O), and CH2NR3bS(O)2, wherein the right side of G1 is attached to ring G;
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, and NR2SO2R2, 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;
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)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, CH2, CH(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;
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.

5. A compound according to claim 3, wherein:
G1 is CH2NHC(O), wherein the right side of G1 is attached to ring G;
A is selected from the group: phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl;
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, and CH2NHSO2CH3provided 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)2phenyl 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;
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)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 subsubstituted 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;
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.

6. A compound according to claim 5, wherein:
A is selected from the group: phenyl, 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, and —(CH2)—5–6 membered carbocycle substituted with 0–2 R4c, 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.

7. A compound according to claim 6, wherein:
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;
R4c is selected from ═O, OH, OCH3, and CH3.

8. A compound according to claim 1, wherein the compound is selected from the group:
5-chloro-N{[1-(2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)phenyl)-5-oxopyrrolidin-3-yl]methyl}thiophene-2-carboxamide;
5-chloro-N-((1-(2-fluoro-4-(2-N,N-dimethylaminomethylphenyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-sulfonamide;
5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((5-oxo- 1-(4-(1-(pyrrolidin- 1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide;
5-chloro-N-((1-(4-(1-((dimethylamino)methyl)cyclopropyl)phenyl)-5-oxopyrrolidin-3-yl)methyl)thiophene-2-carboxamide; and
5-(5-chlorothiophen-2-yl)-N-((5-oxo- 1-(4-(1-(pyrrolidin- 1-ylmethyl)cyclopropyl)phenyl)pyrrolidin-3-yl)methyl)thiophene-2-carboxamide;

or a pharmaceutically acceptable salt form thereof.

9. 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.

10. 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.

11. A method according to claim 10, 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.

12. A method according to claim 10, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.

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

14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3 or a pharmaceutically acceptable salt form thereof.

15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.

16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.

17. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof.

18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof.

19. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt form thereof.

20. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 or a pharmaceutically acceptable salt form thereof.

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

22. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt form thereof.

23. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt form thereof.

24. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 6 or a pharmaceutically acceptable salt form thereof.

25. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt form thereof.

26. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt form thereof.