Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors Number:7,122,557 from the United States Patent and Trademark Office (PTO) owispatent The present application describes sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds and derivatives thereof of Formula I: P.sub.4-P-M-M.sub.4I or pharmaceutically acceptable salt forms thereof, wherein M is a ring, P is an optional ring, and P.sub.4 and M.sub.4 are as defined below. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.<H tetrahydropyrimidino, inhibitors, Sulfonyl, amidin, 7122557.html, Patent, pto, 7122557

Title: Sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds as factor Xa inhibitors

Abstract: The present application describes sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds and derivatives thereof of Formula I: P.sub.4-P-M-M.sub.4I or pharmaceutically acceptable salt forms thereof, wherein M is a ring, P is an optional ring, and P.sub.4 and M.sub.4 are as defined below. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

Patent Number: 7,122,557 Issued on 10/17/2006 to Pinto, et al.

Inventors: Pinto; Donald J. (Kennett Square, PA), Qiao; Jennifer X. (Princeton, NJ), Gungor; Timur (Pennington, NJ), Lam; Patrick Y. S. (Chadds Ford, PA), Li; Yun-Long (Wilmington, DE)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)

Appl. No.: 10/801,518

Filed: March 16, 2004

Current U.S. Class: 514/303 ; 546/120

Current International Class: A61K 31/437 (20060101); C07D 471/04 (20060101)

References Cited [Referenced By]

U.S. Patent Documents


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Foreign Patent Documents


WO 98/28269	Jul., 1998	WO
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Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Freistein; Andrew B.
Attorney, Agent or Firm: Sun; Jing G. Vance; David H.

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefit of U.S. Provisional Application No. 60/455,709, filed Mar. 18, 2003, which is expressly incorporated fully herein by reference.

Claims

What is claimed is:

1. A compound of Formula I: ##STR00202## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; G is a group of formula IIa: ##STR00203## ring D is absent and ring E is phenyl is substituted with R; R is selected from OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, and OCH.sub.2CH.sub.2CH.sub.3; A is phenyl; B is ##STR00204## provided that Z and B are attached to different atoms on A and that the R.sup.4a shown is other than OH; Q.sup.1 and Q.sup.2 are each N; alternatively, one of Q.sup.1 and Q.sup.2 is CR.sup.3 and R.sup.4a is NR.sup.2R.sup.2a or NR.sup.3aB.sub.1, provided that when one of Q.sup.1 and Q.sup.2 is CR.sup.3, then this R.sup.3 group optionally forms a ring with the R.sup.2 group of R.sup.4a, 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).sub.p, and this ring is substituted with 0 1 R.sup.5; ring Q is a 5 8 membered ring consisting of, in addition to the Q.sup.1--CR.sup.4a.dbd.Q.sup.2 group shown, carbon atoms and 0 2 heteroatoms selected from N, O, and S(O).sub.p, and the ring is substituted with an additional 0 2 R.sup.4a; R.sup.1a, at each occurrence, is selected from H, --(CR.sup.3R.sup.3a).sub.r--R.sup.1b, --(CR.sup.3R.sup.3a).sub.r--CR.sup.3R.sup.1bR.sup.1b, --(CR.sup.3R.sup.3a).sub.r--O--(CR.sup.3R.sup.3a).sub.r--R.sup.1b, --(CR.sup.3R.sup.3a).sub.r--NR.sup.2--(CR.sup.3R.sup.3a).sub.r--R.sup.1b, --(CR.sup.3R.sup.3a).sub.r--S(O).sub.p--(CR.sup.3R.sup.3a).sub.r--R.sup.1- b, --(CR.sup.3R.sup.3a).sub.r--CO.sub.2--(CR.sup.3R.sup.3a).sub.r--R.sup.1- b, --(CR.sup.3R.sup.3a).sub.r--C(O)NR.sup.2--(CR.sup.3R.sup.3a).sub.r--R.s- up.1b, --(CR.sup.3R.sup.3a).sub.r--C(O)--(CR.sup.3R.sup.3a).sub.r--R.sup.1- b, --C.sub.2-6 alkenylene-R.sup.1b, --C.sub.2-6 alkynylene-R.sup.1b, and --(CR.sup.3R.sup.3a).sub.r--C(.dbd.NR.sup.1b)NR.sup.3R.sup.1b, provided that R.sup.1a forms other than an N-halo, N--S, O--O, or N--CN bond; R.sup.1b is selected from H, C.sub.1-3 alkyl, F, Cl, Br, I, --CN, --NO.sub.2, --CHO, (CF.sub.2).sub.rCF.sub.3, (CR.sup.3R.sup.3a).sub.rOR.sup.2, NR.sup.2R.sup.2a, C(O)R.sup.2b, CO.sub.2R.sup.2b, OC(O)R.sup.2, CH(CH.sub.2OR.sup.2).sub.2, (CF.sub.2).sub.rCO.sub.2R.sup.2a, S(O).sub.pR.sup.2b, NR.sup.2(CH.sub.2).sub.rOR.sup.2, C(.dbd.NR.sup.2c)NR.sup.2R.sup.2a, NR.sup.2C(O)R.sup.2b, NR.sup.2C(O)NR.sup.2R.sup.2a, NR.sup.2C(O).sub.2R.sup.2a, OC(O)NR.sup.2R.sup.2a, C(O)NR.sup.2R.sup.2a, C(O)NR.sup.2(CH.sub.2).sub.rOR.sup.2, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.2, C(O)NR.sup.2SO.sub.2R.sup.2, C.sub.3-6 carbocycle substituted with 0 2 R.sup.4b, and 5 10 membered heterocycle substituted with 0 2 R.sup.4b and consisting of carbon atoms and from 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p, provided that R.sup.1b forms other than an O--O, N-halo, N--S, or N--CN bond; R.sup.2, at each occurrence, is selected from H, CF.sub.3, C.sub.1-6 alkyl, --(CH.sub.2).sub.r--C.sub.3-10 carbocycle substituted with 0 2 R.sup.4b, and --(CH.sub.2).sub.r-5 10 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.2a, at each occurrence, is selected from H, CF.sub.3, C.sub.1-6 alkyl, --(CH.sub.2).sub.r--C.sub.3-10 carbocycle substituted with 0 2 R.sup.4b, and --(CH.sub.2).sub.r-5 10 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; alternatively, NR.sup.2R.sup.2a forms a 5 or 6 membered saturated, partially saturated, or unsaturated ring substituted with 0 2 R.sup.4b and consisting of: carbon atoms, the nitrogen atom to which R.sup.2 and R.sup.2a are attached, and 0 1 additional heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.2b, at each occurrence, is selected from CF.sub.3, C.sub.1-4 alkoxy substituted with 0 2 R.sup.4b, C.sub.1-6 alkyl substituted with 0 2 R.sup.4b, --(CH.sub.2).sub.r--C.sub.3-10 carbocycle substituted with 0 2 R.sup.4b, and --(CH.sub.2).sub.r-5 10 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.2c, at each occurrence, is selected from CF.sub.3, OH, C.sub.1-4 alkoxy, C.sub.1-6 alkyl, --(CH.sub.2).sub.r--C.sub.3-10 carbocycle substituted with 0 2 R.sup.4b, and --(CH.sub.2).sub.r-5 10 membered heterocycle containing from 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.3, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, benzyl, and phenyl; R.sup.3a, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, benzyl, and phenyl; alternatively, NR.sup.3R.sup.3a forms a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R.sup.3 and R.sup.3a are attached, and 0 1 additional heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.3b, at each occurrence, is selected from H, CF.sub.3, C.sub.1-6 alkyl substituted with 0 2 R.sup.1a, C.sub.2-6 alkenyl substituted with 0 2R.sup.1a, C.sub.2-6 alkynyl substituted with 0 2 R.sup.1a, --(C.sub.0-4 alkyl)-5 10 membered carbocycle substituted with 0 3 R.sup.1a, and --(C.sub.0-4 alkyl)-5 10 membered heterocycle substituted with 0 3 R.sup.1a and consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.3c, at each occurrence, is selected from CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, benzyl, and phenyl; R.sup.3d, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C.sub.1-4 alkyl-phenyl, and C(.dbd.O)R.sup.3c; R.sup.4a, at each occurrence, is selected from H, (CR.sup.3R.sup.3a).sub.rOR.sup.2, (CR.sup.3R.sup.3a).sub.rF, (CR.sup.3R.sup.3a).sub.rBr, (CR.sup.3R.sup.3a).sub.rCl, C.sub.1-4 alkyl, (CR.sup.3R.sup.3a).sub.rCN, (CR.sup.3R.sup.3a).sub.rNO.sub.2, (CR.sup.3R.sup.3a).sub.rNR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rC(O)R.sup.2c, (CR.sup.3R.sup.3a).sub.rNR.sup.2C(O)R.sup.2b, (CR.sup.3R.sup.3a).sub.rC(O)NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rN.dbd.CHOR.sup.3, (CR.sup.3R.sup.3a).sub.rC(O)NH(CH.sub.2).sub.2NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rNR.sup.2C(O)NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rC(.dbd.NR.sup.2)NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rNHC(.dbd.NR.sup.2)NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rSO.sub.2NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rNR.sup.2SO.sub.2NR.sup.2R.sup.2a, (CR.sup.3R.sup.3a).sub.rNR.sup.2SO.sub.2--C.sub.1-4 alkyl, (CR.sup.3R.sup.3a).sub.rC(O)NHSO.sub.2--C.sub.1-4 alkyl, (CR.sup.3R.sup.3a)NR.sup.2SO.sub.2R.sup.5, (CR.sup.3R.sup.3a).sub.rS(O).sub.pR.sup.5a, (CR.sup.3R.sup.3a).sub.r(CF.sub.2).sub.rCF.sub.3, (CR.sup.3R.sup.3a).sub.r-5 6 membered carbocycle substituted with 0 1 R.sup.5, and a (CR.sup.3R.sup.3a).sub.r-5 6 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 1 R.sup.5; R.sup.4b, at each occurrence, is selected from H, .dbd.O, (CH.sub.2).sub.rOR.sup.3, (CH.sub.2).sub.rF, (CH.sub.2).sub.rCl, (CH.sub.2).sub.rBr, (CH.sub.2).sub.rI, C.sub.1-4 alkyl, (CH.sub.2).sub.rCN, (CH.sub.2).sub.rNO.sub.2, (CH.sub.2).sub.rNR.sup.3R.sup.3a, (CH.sub.2).sub.rC(O)R.sup.3, (CH.sub.2).sub.rC(O)OR.sup.3c, (CH.sub.2).sub.rNR.sup.3C(O)R.sup.3a, (CH.sub.2).sub.r--C(O)NR.sup.3R.sup.3a, (CH.sub.2).sub.rNR.sup.3 C(O)NR.sup.3R.sup.3a, (CH.sub.2).sub.r--C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, (CH.sub.2).sub.rNR.sup.3C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, (CH.sub.2).sub.rSO.sub.2NR.sup.3R.sup.3a, (CH.sub.2).sub.rNR.sup.3SO.sub.2NR.sup.3R.sup.3a, (CH.sub.2).sub.rNR.sup.3SO.sub.2--C.sub.1-4 alkyl, (CH.sub.2).sub.rNR.sup.3SO.sub.2CF.sub.3, (CH.sub.2).sub.rNR.sup.3SO.sub.2-phenyl, (CH.sub.2).sub.rS(O).sub.pCF.sub.3, (CH.sub.2).sub.rS(O).sub.p--C.sub.1-4 alkyl, (CH.sub.2).sub.rS(O).sub.p-phenyl, and (CH.sub.2).sub.r(CF.sub.2).sub.rCF.sub.3; R.sup.5, at each occurrence, is selected from H, C.sub.1-6 alkyl, .dbd.O, (CH.sub.2).sub.rOR.sup.3, F, Cl, Br, I, --CN, NO.sub.2, (CH.sub.2).sub.rNR.sup.3R.sup.3a, (CH.sub.2).sub.rC(O)R.sup.3, (CH.sub.2).sub.rC(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, NR.sup.3C(O)NR.sup.3R.sup.3a, CH(.dbd.NOR.sup.3d), C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, NR.sup.3C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2--C.sub.1-4 alkyl, NR.sup.3SO.sub.2CF.sub.3, NR.sup.3SO.sub.2-phenyl, S(O).sub.pCF.sub.3, S(O).sub.p--C.sub.1-4 alkyl, S(O).sub.p-phenyl, (CF.sub.2).sub.rCF.sub.3, phenyl substituted with 0 2 R.sup.6, naphthyl substituted with 0 2 R.sup.6, and benzyl substituted with 0 2 R.sup.6; R.sup.5a, at each occurrence, is selected from C.sub.1-6 alkyl, (CH.sub.2).sub.rOR.sup.3, (CH.sub.2).sub.rNR.sup.3R.sup.3a, (CH.sub.2).sub.rC(O)R.sup.3, (CH.sub.2).sub.rC(O)OR.sup.3c, (CH.sub.2).sub.rNR.sup.3C(O)R.sup.3a, (CH.sub.2).sub.rC(O)NR.sup.3R.sup.3a, (CF.sub.2).sub.rCF.sub.3, phenyl substituted with 0 2 R.sup.6, naphthyl substituted with 0 2 R.sup.6, and benzyl substituted with 0 2 R.sup.6, provided that R.sup.5a does not form a S--N or S(O).sub.p--C(O) bond; R.sup.6, at each occurrence, is selected from H, OH, (CH.sub.2).sub.rOR.sup.2, halo, C.sub.1-4 alkyl, --CN, NO.sub.2, (CH.sub.2).sub.rNR.sup.2R.sup.2a, (CH.sub.2).sub.rC(O)R.sup.2b, NR.sup.2C(O)R.sup.2b, NR.sup.2C(O)NR.sup.2R.sup.2a, C(.dbd.NH)NH.sub.2, NHC(.dbd.NH)NH.sub.2, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2NR.sup.2R.sup.2a, and NR.sup.2SO.sub.2C.sub.1-4 alkyl; p, at each occurrence, is selected from 0, 1, and 2; and r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6.

2. A compound according to claim 1, wherein: R is selected from OH, OCH.sub.3, OCH.sub.2CH.sub.3, and OCH(CH.sub.3).sub.2; B is ##STR00205## ; provided that Z and B are attached to different atoms on A and that the R.sup.4a shown is other than OH; Q.sup.1 and Q.sup.2 are each N; alternatively, one of Q.sup.1 and Q.sup.2 is CR.sup.3 and R.sup.4a is NR.sup.2R.sup.2a or NR.sup.3aB.sub.1, provided that when one of Q.sup.1 and Q.sup.2 is CR.sup.3, then this R.sup.3 group optionally forms a ring with the R.sup.2 group of R.sup.4a, 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).sub.p, and this ring is substituted with 0 1 R.sup.5; ring Q is a 5 6 membered ring consisting of, in addition to the Q.sup.1--CR.sup.4a.dbd.Q.sup.2 group shown, carbon atoms and 0 2 heteroatoms selected from N, O, and S(O).sub.p, and the ring is substituted with an additional 0 2 R.sup.4a; R.sup.1a, at each occurrence, is selected from H, --(CH.sub.2).sub.r--R.sup.1b, --(CH(CH.sub.3)).sub.r--R.sup.1b, --(C(CH.sub.3).sub.2).sub.r--R.sup.1b, --O--(CR.sup.3R.sup.3a).sub.r--R.sup.1b, --NR.sup.2--(CR.sup.3R.sup.3a).sub.r--R.sup.1b, and --S--(CR.sup.3R.sup.3a).sub.r--R.sup.1b, provided that R.sup.1a forms other than an N-halo, N--S, O--O, or N--CN bond; R.sup.1b is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, F, Cl, Br, I, --CN, --CHO, CF.sub.3, OR.sup.2, NR.sup.2R.sup.2a, C(O)R.sup.2b, CO.sub.2R.sup.2b, OC(O)R.sup.2, CO.sub.2R.sup.2a, S(O).sub.pR.sup.2b, NR.sup.2(CH.sub.2).sub.rOR.sup.2, NR.sup.2C(O)R.sup.2b, NR.sup.2C(O)NHR.sup.2, NR.sup.2C(O).sub.2R.sup.2a, OC(O)NR.sup.2R.sup.2a, C(O)NR.sup.2R.sup.2a, C(O)NR.sup.2(CH.sub.2).sub.rOR.sup.2, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.2, C.sub.5-6 carbocycle substituted with 0 2 R.sup.4b, 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).sub.p, and substituted with 0 2 R.sup.4b, provided that R.sup.1b forms other than an O--O, N-halo, N--S, or N--CN bond; R.sup.2, at each occurrence, is selected from H, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, C.sub.5-6 carbocycle substituted with 0 2 R.sup.4b, a --CH.sub.2--C.sub.5-6 carbocyclic group substituted with 0 2 R.sup.4b, and 5 6 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.2a, at each occurrence, is selected from H, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, benzyl substituted with 0 2 R.sup.4b, C.sub.5-6 carbocycle substituted with 0 2 R.sup.4b, and 5 6 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; alternatively, NR.sup.2R.sup.2a forms a 5 or 6 membered saturated, partially saturated, or unsaturated ring substituted with 0 2 R.sup.4b and consisting of: carbon atoms, the nitrogen atom to which R.sup.2 and R.sup.2a are attached, and 0 1 additional heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.2b, at each occurrence, is selected from CF.sub.3, C.sub.1-4 alkoxy, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, benzyl substituted with 0 2 R.sup.4b, C.sub.5-6 carbocycle substituted with 0 2 R.sup.4b, and 5 6 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.2c, at each occurrence, is selected from CF.sub.3, OH, C.sub.1-4 alkoxy, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, benzyl substituted with 0 2 R.sup.4b, C.sub.5-6 carbocycle substituted with 0 2 R.sup.4b, and 5 6 membered heterocycle containing from 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.3, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl, and phenyl; R.sup.3a, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl, and phenyl; alternatively, NR.sup.3R.sup.3a forms a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring consisting of: carbon atoms and the nitrogen atom to which R.sup.3 and R.sup.3a are attached; R.sup.3b, at each occurrence, is selected from H, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, --(C.sub.0-1 alkyl)-5 6 membered carbocycle substituted with 0 1 R.sup.1a, and --(C.sub.0-1 alkyl)-5 6 membered heterocycle substituted with 0 1 R.sup.1a and consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.3c, at each occurrence, is selected from CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl, and phenyl; R.sup.3d, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2-phenyl, CH.sub.2CH.sub.2-phenyl, and C(.dbd.O)R.sup.3c; R.sup.4a, at each occurence, is selected from H, CH.sub.2OR.sup.2, OR.sup.2, C.sub.1-4 alkyl, --CN, CH.sub.2CN, NO.sub.2, CH.sub.2NO.sub.2, NR.sup.2R.sup.2a, CH.sub.2NR.sup.2R.sup.2a, C(O)R.sup.2c, CH.sub.2C(O)R.sup.2c, NR.sup.2C(O)R.sup.2b, (CH.sub.2).sub.rC(O)NR.sup.2R.sup.2a, NR.sup.2C(O)NR.sup.2R.sup.2a, (CH.sub.2).sub.rSO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.5, (CH.sub.2).sub.rS(O).sub.pR.sup.5a, CH.sub.2CF.sub.3, CF.sub.3, 5 6 membered carbocycle substituted with 0 1 R.sup.5, CH.sub.2-5 6 membered carbocycle substituted with 0 1 R.sup.5, a 5 6 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 1 R.sup.5, and a CH.sub.2-5 6 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 1 R.sup.5; R.sup.4b, at each occurrence, is selected from H, .dbd.O, OR.sup.3, CH.sub.2OR.sup.3, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, --CN, NO.sub.2, NR.sup.3R.sup.3a, CH.sub.2NR.sup.3R.sup.3a, C(O)R.sup.3, CH.sub.2C(O)R.sup.3, C(O)OR.sup.3c, CH.sub.2C(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, CH.sub.2NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, CH.sub.2C(O)NR.sup.3R.sup.3a, NR.sup.3C(O)NR.sup.3R.sup.3a, CH.sub.2NR.sup.3C(O)NR.sup.3R.sup.3a, C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, CH.sub.2C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, NR.sup.3C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, CH.sub.2NR.sup.3C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, CH.sub.2SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2NR.sup.3R.sup.3a, CH.sub.2NR.sup.3SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2--C.sub.1-4 alkyl, CH.sub.2NR.sup.3SO.sub.2--C.sub.1-4 alkyl, NR.sup.3SO.sub.2CF.sub.3, CH.sub.2NR.sup.3SO.sub.2CF.sub.3, NR.sup.3SO.sub.2-phenyl, CH.sub.2NR.sup.3SO.sub.2-phenyl, S(O).sub.pCF.sub.3, CH.sub.2S(O).sub.pCF.sub.3, S(O).sub.p--C.sub.1-4 alkyl, CH.sub.2S(O).sub.p--C.sub.1-4 alkyl, S(O).sub.p-phenyl, CH.sub.2S(O).sub.p-phenyl, CF.sub.3, and CH.sub.2CF.sub.3; R.sup.5, at each occurrence, is selected from H, .dbd.O, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, OR.sup.3, CH.sub.2OR.sup.3, F, Cl, --CN, NO.sub.2, NR.sup.3R.sup.3a, CH.sub.2NR.sup.3R.sup.3a, C(O)R.sup.3, CH.sub.2C(O)R.sup.3, C(O)OR.sup.3c, CH.sub.2C(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, NR.sup.3C(O)NR.sup.3R.sup.3a, CH(.dbd.NOR.sup.3d), C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, NR.sup.3C(.dbd.NR.sup.3)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, NR.sup.3 SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2--C.sub.1-4 alkyl, NR.sup.3SO.sub.2CF.sub.3, NR.sup.3SO.sub.2-phenyl, S(O).sub.pCF.sub.3, S(O).sub.p--C.sub.1-4 alkyl, S(O).sub.p-phenyl, CF.sub.3, phenyl substituted with 0 2 R.sup.6, naphthyl substituted with 0 2 R.sup.6, and benzyl substituted with 0 2 R.sup.6; and R.sup.6, at each occurrence, is selected from H, OH, OR.sup.2, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, --CN, NO.sub.2, NR.sup.2R.sup.2a, CH.sub.2NR.sup.2R.sup.2a, C(O)R.sup.2b, CH.sub.2C(O)R.sup.2b, NR.sup.2C(O)R.sup.2b, NR.sup.2C(O)NR.sup.2R.sup.2a, C(.dbd.NH)NH.sub.2, NHC(.dbd.NH)NH.sub.2, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2NR.sup.2R.sup.2a, and NR.sup.2SO.sub.2C.sub.1-4 alkyl.

3. A compound according to claim 2, wherein: G is is 4-methoxy-phenyl, G is 4-methoxy-phenyl; B is ##STR00206## ; provided that Z and B are attached to different atoms on A and that the R.sup.4a shown is other than OH; ring Q is a 5 6 membered ring consisting of, in addition to the N--CR.sup.4a.dbd.N group shown, carbon atoms and 0 2 heteroatoms selected from N, O, and S(O).sub.p, and the ring is substituted with an additional 0 2 R.sup.4a; R.sup.1a is selected from H, R.sup.1b, CH(CH.sub.3)R.sup.1b, C(CH.sub.3).sub.2R.sup.1b, CH.sub.2R.sup.1b, and CH.sub.2CH.sub.2R.sup.1b, provided that R.sup.1a forms other than an N-halo, N--S, or N--CN bond; R.sup.1b is selected from H, CH.sub.3, CH.sub.2CH.sub.3, F, Cl, Br, --CN, --CHO, CF.sub.3, OR.sup.2, NR.sup.2R.sup.2a, C(O)R.sup.2b, CO.sub.2R.sup.2b, OC(O)R.sup.2, CO.sub.02R.sup.2a, S(O).sub.pR.sup.2b, NR.sup.2(CH.sub.2) .sub.rOR.sup.2, NR.sup.2C(O)R.sup.2b, C(O)NR.sup.2R.sup.2a, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.2, phenyl substituted with 0 2 R.sup.4b, 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).sub.p, and substituted with 0 2 R.sup.4b, provided that R.sup.1b forms other than an O--O, N-halo, N--S, or N--CN bond; R.sup.2, at each occurrence, is selected from H, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, phenyl substituted with 0 2 R.sup.4b, a benzyl substituted with 0 2 R.sup.4b, 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).sub.p and substituted with 0 2 R.sup.4b; R.sup.2a, at each occurrence, is selected from H, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl substituted with 0 2 R.sup.4b, phenyl substituted with 0 2 R.sup.4b, 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).sub.p and substituted with 0 2 R.sup.4b; alternatively, NR.sup.2R.sup.2a forms a 5 or 6 membered saturated, partially saturated, or unsaturated ring substituted with 0 2 R.sup.4b and consisting of: carbon atoms, the nitrogen atom to which R.sup.2 and R.sup.2a are attached, and 0 1 additional heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.2b, at each occurrence, is selected from CF.sub.3, C.sub.1-4 alkoxy, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl substituted with 0 2 R.sup.4b, phenyl substituted with 0 2 R.sup.4b, 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).sub.p and substituted with 0 2 R.sup.4b; R.sup.2c, at each occurrence, is selected from CF.sub.3, OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl substituted with 0 2 R.sup.4b, phenyl substituted with 0 2 R.sup.4b, and 5 6 membered aromatic heterocycle containing from 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4b; R.sup.3b, at each occurrence, is selected from H, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, and CH(CH.sub.3).sub.2; R.sup.4a, at each occurrence, is selected from H, OR.sup.2, CH.sub.2OR.sup.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, --CN, NO.sub.2, NR.sup.2R.sup.2a, CH.sub.2NR.sup.2R.sup.2a, C(O)R.sup.2c, NR.sup.2C(O)R.sup.2b, C(O)NR.sup.2R.sup.2a, NR.sup.2C(O)NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.5, SO.sub.2NR.sup.2R.sup.2a, 6 membered carbocycle substituted with 0 1 R.sup.5, 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).sub.p and substituted with 0 1 R.sup.5; R.sup.4b, at each occurrence, is selected from H, .dbd.O, OR.sup.3, CH.sub.2OR.sup.3, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, --CN, NO.sub.2, NR.sup.3R.sup.3a, CH.sub.2NR.sup.3R.sup.3a, C(O)R.sup.3, CH.sub.2C(O)R.sup.3, C(O)OR.sup.3c, CH.sub.2C(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, CH.sub.2NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, CH.sub.2C(O)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, CH.sub.2SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2--C.sub.1-4 alkyl, CH.sub.2NR.sup.3SO.sub.2--C.sub.1-4 alkyl, NR.sup.3SO.sub.2-phenyl, CH.sub.2NR.sup.3SO.sub.2-phenyl, S(O).sub.pCF.sub.3, CH.sub.2S(O).sub.pCF.sub.3, S(O).sub.p--C.sub.1-4 alkyl, CH.sub.2S(O).sub.p--C.sub.1-4 alkyl, S(O).sub.p-phenyl, CH.sub.2S(O).sub.p-phenyl, and CF.sub.3; R.sup.5, at each occurrence, is selected from H, .dbd.O, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, OR.sup.3, CH.sub.2OR.sup.3, F, Cl, --CN, NO.sub.2, NR.sup.3R.sup.3a, CH.sub.2NR.sup.3R.sup.3a, C(O)R.sup.3, CH.sub.2C(O)R.sup.3, C(O)OR.sup.3c, CH.sub.2C(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, CF.sub.3, phenyl substituted with 0 2 R.sup.6, naphthyl substituted with 0 2 R.sup.6, and benzyl substituted with 0 2 R.sup.6; and R.sup.6, at each occurrence, is selected from H, OH, OR.sup.2, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, --CN, NO.sub.2, NR.sup.2R.sup.2a, CH.sub.2NR.sup.2R.sup.2a, C(O)R.sup.2b, CH.sub.2(O)R.sup.2b, NR.sup.2C(O)R.sup.2b, SO.sub.2NR.sup.2R.sup.2a, and NR.sup.2SO.sub.2C.sub.1-4 alkyl.

4. A compound according to claim 3, wherein: B is ##STR00207## ; provided that Z and B are attached to different atoms on A and that the R.sup.4a shown is other than OH; ring Q is a 5 6 membered ring consisting of, in addition to the N--CR.sup.4a.dbd.N group shown, carbon atoms and 0 1 heteroatoms selected from N, O, and S(O).sub.p, and the ring is substituted with an additional 0 2 R.sup.4a; R.sup.1a, at each occurrence, is selected from H, R.sup.1b, CH(CH.sub.3)R.sup.1b, C(CH.sub.3).sub.2R.sup.1b, and CH.sub.2R.sup.1b, provided that R.sup.1a forms other than an N-halo, N--S, or N--CN bond; R.sup.1b is selected from CH.sub.3, CH.sub.2CH.sub.3, F, Cl, Br, --CN, CF.sub.3, OR.sup.2, NR.sup.2R.sup.2a, C(O)R.sup.2b, CO.sub.2R.sup.2b, CO.sub.2R.sup.2a, S(O).sub.pR.sup.2b, C(O)NR.sup.2R.sup.2a, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.2, 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).sub.p, and substituted with 0 2 R.sup.4b, provided that R.sup.1b forms other than an O--O, N-halo, N--S, or N--CN bond; R.sup.2, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, phenyl substituted with 0 1 R.sup.4b, benzyl substituted with 0 1 R.sup.4b, 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).sub.p and substituted with 0 1 R.sup.4b; R.sup.2a, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl substituted with 0 1 R.sup.4b, phenyl substituted with 0 1 R.sup.4b, 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).sub.p and substituted with 0 1 R.sup.4b; alternatively, NR.sup.2R.sup.2a forms a 5 or 6 membered saturated, partially saturated, or unsaturated ring substituted with 0 1 R.sup.4b and consisting of: carbon atoms, the nitrogen atom to which R.sup.2 and R.sup.2a are attached, and 0 1 additional heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.2b, at each occurrence, is selected from OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl substituted with 0 1 R.sup.4b, phenyl substituted with 0 1 R.sup.4b, 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).sub.p and substituted with 0 1 R.sup.4b; R.sup.2c, at each occurrence, is selected from OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, benzyl substituted with 0 1 R.sup.4b, phenyl substituted with 0 1 R.sup.4b, and 5 6 membered aromatic heterocycle containing from 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 1 R.sup.4b; R.sup.3b, at each occurrence, is selected from H and CH.sub.3; R.sup.4a, at each occurrence, is selected from H, OR.sup.2, CH.sub.2OR.sup.2, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2CH.sub.3, C(CH.sub.3).sub.3, NR.sup.2R.sup.2a, CH.sub.2NR.sup.2R.sup.2a, C(O)R.sup.2c, NR.sup.2C(O)R.sup.2b, C(O)NR.sup.2R.sup.2a, SO.sub.2NR.sup.2R.sup.2a, NR.sup.2SO.sub.2R.sup.5, phenyl substituted with 0 1 R.sup.5, and a 5 6 membered heterocycle consisting of: carbon atoms and 1 heteroatom selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 1 R.sup.5; R.sup.4b, at each occurrence, is selected from H, .dbd.O, OR.sup.3, CH.sub.2OR.sup.3, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, --CN, NO.sub.2, NR.sup.3R.sup.3a, CH.sub.2NR.sup.3R.sup.3a, C(O)R.sup.3, C(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2--C.sub.1-4 alkyl NR.sup.3SO.sub.2-phenyl, S(O).sub.p--C.sub.1-4 alkyl, S(O).sub.p-phenyl, and CF.sub.3; R.sup.5, at each occurrence, is selected from H, .dbd.O, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, OR.sup.3, NR.sup.3R.sup.3a, C(O)R.sup.3, NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, and phenyl substituted with 0 2 R.sup.6; and, R.sup.6, at each occurrence, is selected from H, OH, OR.sup.2, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, --CN, NO.sub.2, NR.sup.2R.sup.2a, CH.sub.2NR.sup.2R.sup.2a, C(O)R.sup.2b, CH.sub.2C(O)R.sup.2b, NR.sup.2C(O)R.sup.2b, and SO.sub.2NR.sup.2R.sup.2a.

5. A compound according to claim 4, wherein: B, provided that Z and B are attached to different atoms on A and that the R.sup.4a shown is other than OH, is; ##STR00208## R.sup.1a, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH.sub.2F, CH.sub.2Cl, Br, CH.sub.2Br, --CN, CH.sub.2CN, CF.sub.3, CH.sub.2CF.sub.3, OCH.sub.3, CH.sub.2OH, C(CH.sub.3).sub.2OH, CH.sub.2OCH.sub.3, NH.sub.2, CH.sub.2NH.sub.2, NHCH.sub.3, CH.sub.2NHCH.sub.3, N(CH.sub.3).sub.2, CH.sub.2N(CH.sub.3).sub.2, CO.sub.2H, COCH.sub.3, CO.sub.2CH.sub.3, CH.sub.2CO.sub.2CH.sub.3, SCH.sub.3, CH.sub.2SCH.sub.3, S(O)CH.sub.3, CH.sub.2S(O)CH.sub.3, S(O).sub.2CH.sub.3, CH.sub.2S(O).sub.2CH.sub.3, C(O)NH.sub.2, CH.sub.2C(O)NH.sub.2, SO.sub.2NH.sub.2, CH.sub.2SO.sub.2NH.sub.2, NHSO.sub.2CH.sub.3, CH.sub.2NHSO.sub.2CH.sub.3, 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, CH.sub.2-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, CH.sub.2-1,2,3,4-tetrazol-1-yl, and CH.sub.2-1,2,3,4-tetrazol-5-yl, provided that R.sup.1a forms other than an N-halo, N--S, or N--CN bond; R.sup.2, at each occurrence, is selected from H, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, phenyl substituted with 0 1 R.sup.4b, benzyl substituted with 0 1 R.sup.4b, and 5 membered aromatic heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 1 R.sup.4b; R.sup.2a, at each occurrence, is selected from H, CH.sub.3, and CH.sub.2CH.sub.3; alternatively, NR.sup.2R.sup.2a forms a 5 or 6 membered saturated, partially saturated, or unsaturated ring substituted with 0 1 R.sup.4b and consisting of: carbon atoms, the nitrogen atom to which R.sup.2 and R.sup.2a are attached, and 0 1 additional heteroatoms selected from the group consisting of N, O, and S(O).sub.p; R.sup.2b, at each occurrence, is selected from OCH.sub.3, OCH.sub.2CH.sub.3, CH.sub.3, and CH.sub.2CH.sub.3; R.sup.2c, at each occurrence, is selected from OH, OCH.sub.3, OCH.sub.2CH.sub.3, CH.sub.3, and CH.sub.2CH.sub.3; R.sup.4a, at each occurrence, is selected from H, OCH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, NR.sup.2R.sup.2a, NR.sup.2C(O)R.sup.2b, NR.sup.2SO.sub.2R.sup.5, phenyl, 2-oxo-pyrrolidinyl, and 2-oxo-piperidinyl; R.sup.4b, at each occurrence, is selected from H, .dbd.O, OR.sup.3, CH.sub.2OR.sup.3, F, Cl, CH.sub.3, CH.sub.2CH.sub.3, NR.sup.3R.sup.3a, CH.sub.2NR.sup.3R.sup.3a, C(O)R.sup.3, C(O)OR.sup.3c, NR.sup.3C(O)R.sup.3a, C(O)NR.sup.3R.sup.3a, SO.sub.2NR.sup.3R.sup.3a, NR.sup.3SO.sub.2-phenyl, S(O).sub.2CH.sub.3, S(O).sub.2-phenyl, and CF.sub.3; and R.sup.5, at each occurrence, is selected from CH.sub.3 and CH.sub.2CH.sub.3.

6. A compound according to claim 5, wherein: A is ##STR00209## ; and

7. A compound according to claim 6, wherein: A-B is selected from: ##STR00210##

8. A compound according to claim 1, wherein the compound is selected from the group: 6-[4-(5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1-(4-methoxy-phenyl)-3-trifl- uoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 1-(4-methoxy-phenyl)-6-[4-(2-methyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl- ]-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 6-[4-(2-ethyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1-(4-methoxy-phenyl)- -3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 6-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1-(4-methoxy-phe- nyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 1-(4-methoxy-phenyl)-6-[4-(2-phenyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl- ]-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 6-[4-(2-amino-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1-(4-methoxy-phenyl)- -3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; N-(1-{4-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-- pyrazolo[3,4-c]pyridin-6-yl]-phenyl}-1,4,5,6-tetrahydro-pyrimidin-2-yl)-me- thanesulfonamide; (1-{4-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-py- razolo[3,4-c]pyridin-6-yl]-phenyl}-1,4,5,6-tetrahydro-pyrimidin-2-yl)-carb- amic acid methyl ester; N-(1-{4-[1-(4-methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-- pyrazolo[3,4-c]pyridin-6-yl]-phenyl}-1,4,5,6-tetrahydro-pyrimidin-2-yl)-ac- etamide; 1-(4-methoxy-phenyl)-6-{4-[2-(2-oxo-piperidin-1-yl)-5,6-dihydro-4- H-pyrimidin-1-yl]-phenyl}-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,- 4-c]pyridin-7-one; 1-(4-methoxy-phenyl)-6-{4-[2-(2-oxo-pyrrolidin-1-yl)-5,6-dihydro-4H-pyrim- idin-1-yl]-phenyl}-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyr- idin-7-one; 1-(4-methoxy-phenyl)-6-[4-(2-methyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl- ]-3-cyano-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 6-[4-(2-amino-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1-(4-methoxy-phenyl)- -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile; N-(1-{4-[3-cyano-1-(4-methoxy-phenyl)-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3- ,4-c]pyridin-6-yl]-phenyl}-1,4,5,6-tetrahydro-pyrimidin-2-yl)-methanesulfo- namide; N-(1-{4-[3-cyano-1-(4-methoxy-phenyl)-7-oxo-1,4,5,7-tetrahydro-pyr- azolo[3,4-c]pyridin-6-yl]-phenyl}-1,4,5,6-tetrahydro-pyrimidin-2-yl)-N-met- hyl-methanesulfonamide; N-(1-{4-[3-cyano-1-(4-methoxy-phenyl)-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3- ,4-c]pyridin-6-yl]-phenyl}-1,4,5,6-tetrahydro-pyrimidin-2-yl)-acetamide; 6-[4-(2-methoxy-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-1-(4-methoxy-pheny- l)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile; 6-[4-(5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-methanesulfonyl-1-(4-metho- xy-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 3-methanesulfonyl-1-(4-methoxy-phenyl)-6-[4-(2-methyl-5,6-dihydro-4H-pyri- midin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 6-[4-(2-isopropyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-methanesulfony- l-1-(4-methoxy-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 3-methanesulfonyl-1-(4-methoxy-phenyl)-6-[4-(2-phenyl-5,6-dihydro-4H-pyri- midin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 6-[4-(2-amino-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-methanesulfonyl-1-- (4-methoxy-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 3-methanesulfonyl-1-(4-methoxy-phenyl)-6-{4-[2-(2-oxo-piperidin-1-yl)-5,6- -dihydro-4H-pyrimidin-1-yl]-phenyl}-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyri- din-7-one; 6-[4-(5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-isopropoxy-1-(4-- methoxy-phenyl)-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 3-{6-[4-(2-amino-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]-3-methanesulfonyl- -7-oxo-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamide; 3-{3-methanesulfonyl-6-[4-(2-methyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl- ]-7-oxo-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl}-benzamide; 1-(3-chloro-phenyl)-6-[4-(2-methyl-5,6-dihydro-4H-pyrimidin-1-yl)-phenyl]- -3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; 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.

Description

FIELD OF THE INVENTION

This invention relates generally to sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds 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

U.S. Pat. Nos. 3,365,459, 3,340,269, and 3,423,414 illustrate anti-inflammatory inhibitors of the following formula:

##STR00001## wherein A is 2 3 carbon atoms, X can be O, and R.sup.1 and R.sup.3 can be substituted or unsubstituted aromatic groups. None of these patents, however, exemplify or suggest compounds of the present invention.

U.S. Pat. No. 5,342,851 depicts thiazole platelet aggregation inhibitors including those of the following formula:

##STR00002## wherein A is a linker, B can be a linker or a ring, Q is a ring or an amino group, R, R.sub.1, and R.sub.3 are a variety of groups. This patent, however, does not exemplify or suggest compounds of the present invention.

WO00/39131 describes heterobicyclic Factor Xa inhibitors of which the following is an example formula:

##STR00003## wherein Z is C or N, G is a mono- or bicyclic group, A is a cyclic moiety and B is a basic group or a cyclic moiety. Compounds specifically described in WO00/39131 are not considered to be part of the present invention.

WO98/28269, WO98/28282, WO99/32454, U.S. Pat. Nos. 6,020,357, and 6,271,237 describe Factor Xa inhibitors of the following formula:

##STR00004## wherein ring M is a heterocycle, Z is a linker, A is a ring, B is a basic or cyclic group, D is a basic moiety, and E is a ring. Compounds specifically described in WO98/28269, WO98/28282, WO99/32454, U.S. Pat. Nos. 6,020,357, and 6,271,237 are not considered to be part of the present invention.

WO98/57951 describes Factor Xa inhibitors of the following formula:

##STR00005## wherein ring M can be a variety of heterocycles and rings D-E represent a heterobicyclic group. Compounds specifically described in WO98/57951 are not considered to be part of the present invention.

WO98/57934 and U.S. Pat. No. 6,060,491 describe Factor Xa inhibitors of the following formula:

##STR00006## wherein ring M is a 6-membered heteroaryl, Z is a linker, A is a ring, B is a basic or cyclic group, D is a basic moiety, and E is a ring. Compounds specifically described in WO98/57934 and U.S. Pat. No. 6,060,491 are not considered to be part of the present invention.

WO98/57937 and U.S. Pat. No. 5,998,424 describe Factor Xa inhibitors of the following formula:

##STR00007## wherein ring M is a variety of rings, ring D is an aromatic ring, and R and E are non-basic groups. Compounds specifically described in WO98/57937 and U.S. Pat. No. 5,998,424 are not considered to be part of the present invention.

WO99/50255 and U.S. Pat. No. 6,191,159 describe pyrazoline and triazoline Factor Xa inhibitors of the following formulas:

##STR00008## Compounds specifically described in WO99/50255 and U.S. Pat. No. 6,191,159 are not considered to be part of the present invention.

WO00/59902 describes Factor Xa inhibitors of the following formula:

##STR00009## wherein ring M can be a variety of rings all of which are substituted with Z-A-B, Z is a linker, A is a ring, B is a sulfonyl-containing heterobicycle, and rings D-E represent a heterobicyclic group or a 6-membered ring. Compounds specifically described in WO00/59902 are not considered to be part of the present invention.

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

WO01/05784 describes Factor Xa inhibitors of the following formulas:

##STR00010## wherein Z is C or N, G is a mono- or bicyclic ring M, A is a linker, B is a basic or cyclic group. Compounds specifically described in WO01/05784 are not considered to be part of the present invention.

WO00/39108 describes Factor Xa inhibitors of the following formula:

##STR00011## wherein ring M can be a variety of heterocycles and rings D-E represent a heterobicyclic group. Compounds specifically described in WO00/39108 are not considered to be part of the present invention.

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

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca.sup.2+ 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 sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds 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 sulfonyl-amidino-containing and tetrahydropyrimidino-containing compounds of Formula I: P.sub.4-P-M-M.sub.4 I wherein P.sub.4, P, M, and M.sub.4 are defined below, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.

DETAILED DESCRIPTION

In a first aspect, the present invention provides a novel compound of formula I: P.sub.4-P-M-M.sub.4 I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

M is a 3 10 membered carbocycle or a 4 10 membered heterocycle, consisting of: carbon atoms and 1 3 heteroatoms selected from O, S(O).sub.p, N, and NZ.sup.2;

ring M is substituted with 0 3 R.sup.1a and 0 2 carbonyl groups, and there are 0 3 ring double bonds;

P is fused onto ring M and is a 5, 6, or 7 membered carbocycle or a 5, 6, or 7 membered heterocycle, consisting of: carbon atoms and 1 3 heteroatoms selected from O, S(O).sub.p, and N;

ring P is substituted with 0 3 R.sup.1a and 0 2 carbonyl groups, and there are 0 3 ring double bonds;

alternatively, ring P is absent and P.sub.4 is directly attached to ring M, provided that when ring P is absent, P.sub.4 and M.sub.4 are attached to the 1,2, 1,3, or 1,4 positions of ring M;

one of P.sub.4 and M.sub.4 is -Z-A-B and the other -G.sub.1-G;

G is a group of formula IIa or IIb:

##STR00012##

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).sub.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).sub.p, wherein the 5 6 membered heterocycle is substituted with 0 2 carbonyls and 1 2 R and there are 0 3 ring double bonds;

R is selected from H, C.sub.1-4 alkyl, F, Cl, Br, I, OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3, --CN, NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, C(.dbd.NH)NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NH(C.sub.1-3 alkyl), CH.sub.2N(C.sub.1-3 alkyl).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH(C.sub.1-3 alkyl), CH.sub.2CH.sub.2N(C.sub.1-3 alkyl).sub.2, C(.dbd.NR.sup.8)NR.sup.7R.sup.9, NHC(.dbd.NR.sup.8)NR.sup.7R.sup.9, ONHC(.dbd.NR.sup.8)NR.sup.7R.sup.9, NR.sup.8CH(.dbd.NR.sup.7), (CR.sup.8R.sup.9).sub.tC(O)H, (CR.sup.8R.sup.9).sub.tC(O)R.sup.2c, (CR.sup.8R.sup.9).sub.tNR.sup.7R.sup.8, (CR.sup.8R.sup.9).sub.tC(O)NR.sup.7R.sup.8, (CR.sup.8R.sup.9).sub.tNR.sup.7C(O)R.sup.7, (CR.sup.8R.sup.9).sub.tOR.sup.3, (CR.sup.8R.sup.9).sub.tS(O).sub.pNR.sup.7R.sup.8, (CR.sup.8R.sup.9).sub.tNR.sup.7S(O).sub.pR.sup.7, (CR.sup.8R.sup.9).sub.tSR.sup.3, (CR.sup.8R.sup.9).sub.tS(O)R.sup.3, (CR.sup.8R.sup.9).sub.tS(O).sub.2R.sup.3, and OCF.sub.3;

alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;

A is selected from: C.sub.3-10 carbocycle substituted with 0 2 R.sup.4, and 5 12 membered heterocycle consisting of: carbon atoms and 1 4 heteroatoms selected from the group consisting of N, O, and S(O).sub.p and substituted with 0 2 R.sup.4;

B is selected from

##STR00013## provided that Z and B are attached to different atoms on A and that the R.sup.4a shown is other than OH;

Q.sup.1 and Q.sup.2 are each N;

alternatively, one of Q.sup.1 and Q.sup.2 is CR.sup.3 and R.sup.4a is NR.sup.2R.sup.2a or NR.sup.3aB.sub.1, provided that when one of Q.sup.1 and Q.sup.2 is CR.sup.3, then this R.sup.3 group optionally forms a ring with the R.sup.2 group of R.sup.4a, 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).sub.p, and this ring is substituted with 0 1 R.sup.5;

ring Q is a 5 8 membered ring consisting of, in addition to the Q.sup.1--CR.sup.4a=Q.sup.2 group shown, carbon atoms and 0 2 heteroatoms selected from N, O, and S(O).sub.p, and the ring is substituted with an additional 0 2 R.sup.4a;

B.sub.1 is selected from SO.sub.2R.sup.3b, C(O)R.sup.3b, SO.sub.2NR.sup.3R.sup.3b, C(O)NR.sup.3R.sup.3b, OR.sup.2, SR.sup.2, --CN, and NO.sub.2;

B.sub.2 is NR.sup.2R.sup.2d or CR.sup.3R.sup.2R.sup.2d;

alternatively, CR.sup.3R.sup.2R.sup.2d