Heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity Number:7,417,045 from the United States Patent and Trademark Office (PTO) owispatent The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prod rug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: ##STR00001## or a pharmaceutically acceptable salt, solvate or ester thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, zenograft rejection), infectious diseases (e.g, tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.<H Heterocyclic, substituted, Heterocyclic, su, 7417045.html, Patent, pto, 7417045

Title: Heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity

Abstract: The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prod rug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: ##STR00001## or a pharmaceutically acceptable salt, solvate or ester thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, zenograft rejection), infectious diseases (e.g, tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

Patent Number: 7,417,045 Issued on 08/26/2008 to Anilkumar, et al.

Inventors: Anilkumar; Gopinadhan N. (Edison, NJ), Zeng; Qingbei (Edison, NJ), Rosenblum; Stuart B. (West Orange, NJ), Kozlowski; Joseph A. (Princeton, NJ), McGuinness; Brian F. (Plainsboro, NJ), Hobbs; Douglas W. (Yardley, PA)
Assignee: Schering Corporation (Kenilworth, NJ)
Pharmacopeia Inc. (Princeton, NJ)

Appl. No.: 11/353,609

Filed: February 14, 2006

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
60653332	Feb., 2005

Current U.S. Class: 514/252.12 ; 544/358; 544/359

Current International Class: A61K 31/497 (20060101); C07D 241/04 (20060101); C07D 295/00 (20060101); C07D 403/00 (20060101)

Field of Search: 544/358,359 514/252.12

References Cited [Referenced By]

U.S. Patent Documents


2006/0276480	December 2006	Wong et al.

Foreign Patent Documents


WO 00/66558	Nov., 2000	WO
WO 2004/074287	Sep., 2004	WO
WO 2005/003127	Jan., 2005	WO

Other References

West, Anthony R., Solid State Chemistry and Its Applications, Wiley, New York, 1988., p. 365. cited by examiner .
International Search Report for International Application No. PCT/US2006/005128, mailed Jun. 22, 2006 (4pgs.). cited by other.

Primary Examiner: Kifle; Bruck
Assistant Examiner: Leeser; Erich A
Attorney, Agent or Firm: Banerjee; Krishna G. Kalyanaraman; Palaiyur S.

Parent Case Text

REFERENCE TO PRIORITY APPLICATIONS

This Application claims the benefit of U.S. Provisional Application Ser. No. 60/653,332 filed Feb. 16, 2005, which is incorporated herein in its entirety by reference.

Claims

What is claimed is:

1. A compound having the structure shown in Formula 1 ##STR00258## or a pharmaceutically acceptable salt, wherein: Z is N, NO, or NOH; G represents a 5-membered heteroaryl or heterocyclenyl ring containing at least one --C.dbd.N-- moiety as part of said heteroaryl or heterocyclenyl ring, said heteroaryl or heterocyclenyl ring optionally additionally containing on the ring one or more moieties which can be the same or different, each being independently selected from the group consisting of N, N(.fwdarw.O), O, S, S(O) and S(O.sub.2), further wherein said heteroaryl or heterocyclenyl ring can be either (i) unsubstituted, or (ii) optionally independently substituted on one or more ring carbon atoms with one or more R.sup.9 substituents, or on one or more ring nitrogen atoms with one or more R.sup.8 substituents, wherein said R.sup.8 and R.sup.9 substituents can be the same or different; R.sup.3, R.sup.4, R.sup.6 and R.sup.29 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, --CN, CF.sub.3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, --N.dbd.CH--(R.sup.31), --C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30).sub.2, --OR.sup.30, --SO.sub.2(R.sup.31), --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2 and --N(R.sup.30)C(.dbd.O)R.sup.31; the R.sup.8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qC(.dbd.O)OR.sup.31, and --(CH.sub.2).sub.qSO.sub.2NHR.sup.31; the R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.S)N(R.sup.30).sub.2, --C(.dbd.O)alkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, --N(R.sup.30).sub.2, --N(R.sup.30)S(O.sub.2)R.sup.31, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --OR.sup.30, --SO.sub.2(R.sup.31), --SO.sub.2N(R.sup.30).sub.2, .dbd.O and .dbd.S; the R.sup.10 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, --CO.sub.2H, hydroxyalkyl, --C(.dbd.O)N(R.sup.30).sub.2, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --OR.sup.30, halogen, .dbd.O, and --C(.dbd.O)R.sup.31; the R.sup.11 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, CO.sub.2H, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --OR.sup.30, halogen, .dbd.O, and --C(.dbd.O)R.sup.31; R.sup.12 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, --CN, --C(.dbd.O)N(R.sup.30).sub.2, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31 and --S(O.sub.2)R.sup.31; ring D is a five to nine membered cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms independently selected from O, S or N, wherein ring D is unsubstituted or optionally substituted with 1-5 independently selected R.sup.20 moieties; the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, --alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.NR.sup.30)NHR.sup.30, --C(.dbd.NOH)N(R.sup.30).sub.2, --C(.dbd.NOR.sup.31)N(R.sup.30).sub.2, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)S(O).sub.2N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, --SR.sup.30, --SO.sub.2N(R.sup.30).sub.2, --SO.sub.2(R.sup.31), --OSO.sub.2(R.sup.31), and --OSi(R.sup.30).sub.3; or alternatively two R.sup.20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 R.sup.21 moieties; the R.sup.21 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31 , --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.NR.sup.30)NHR.sup.30, --C(.dbd.NOH)N(R.sup.30).sub.2, --C(.dbd.NOR.sup.31)N(R.sup.30).sub.2, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)S(O).sub.2N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, --SR.sup.30, --SO.sub.2N(R.sup.30).sub.2, --SO.sub.2(R.sup.31), --OSO.sub.2(R.sup.31), and --OSi(R.sup.30).sub.3; Y is selected from the group consisting of --(CR.sup.13R.sup.13).sub.r--, --CHR.sup.13C(.dbd.O)--, --(CHR.sup.13).sub.rO--, --(CHR.sup.13).sub.rN(R.sup.30)--, --C(.dbd.O)--, --C(.dbd.NR.sup.30)--, --C(.dbd.N--OR.sup.30)--, --CH(C(.dbd.O)NHR.sup.30)--, CH-heteroaryl-, --C(R.sup.13R.sup.13).sub.rC(R.sup.13).dbd.C(R.sup.13)--, --(CHR.sup.13).sub.rC(.dbd.O)-- and --(CHR.sup.13).sub.rN(H)C(.dbd.O)--; or alternatively Y is cycloalkyl, heterocyclenyl, or heterocyclyl wherein the cycloalkyl, heterocyclenyl, or heterocyclyl is fused with ring D; the R.sup.13 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, --CN, --CO.sub.2H, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --(CHR.sup.30).sub.qOH, --(CHR.sup.30).sub.qOR.sup.31, --(CHR.sup.30).sub.qNH.sub.2, --(CH R.sup.30).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, --NH.sub.2, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --OH, OR.sup.30 , --SO.sub.2N(R.sup.30).sub.2, and --SO.sub.2(R.sup.31); the R.sup.30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOalkyl, --(CH.sub.2).sub.qOalkylaryl, --(CH.sub.2).sub.qOaryl, --(CH.sub.2).sub.qOaralkyl, --(CH.sub.2).sub.qOcycloalkyl, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHalkyl, --(CH.sub.2).sub.qN(alkyl).sub.2, --(CH.sub.2).sub.qNHalkylaryl, --(CH.sub.2).sub.qNHaryl, --(CH.sub.2).sub.qNHaralkyl, --(CH.sub.2).sub.qNHcycloalkyl, --(CH.sub.2).sub.qC(.dbd.O)NHalkyl, --(CH.sub.2).sub.qC(.dbd.O)N(alkyl).sub.2, --(CH.sub.2).sub.qC(.dbd.O)NHalkylaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaralkyl, --(CH.sub.2).sub.qC(.dbd.O)NHcycloalkyl, --(CH.sub.2).sub.qSO.sub.2alkyl, --(CH.sub.2).sub.qSO.sub.2alkylaryl, --(CH.sub.2).sub.qSO.sub.2aryl, --(CH.sub.2).sub.qSO.sub.2aralkyl, --(CH.sub.2).sub.qSO.sub.2cycloalkyl, --(CH.sub.2).sub.qNSO.sub.2alkyl, --(CH.sub.2).sub.qNSO.sub.2alkylaryl, --(CH.sub.2).sub.qNSO.sub.2aryl, --(CH.sub.2).sub.qNSO.sub.2aralkyl, --(CH.sub.2).sub.qNSO.sub.2cycloalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkylaryl, --(CH.sub.2).sub.qSO.sub.2NHaryl, --(CH.sub.2).sub.qSO.sub.2NHaralkyl, --(CH.sub.2).sub.qSO.sub.2NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl; the R.sup.31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOalkyl, --(CH.sub.2).sub.qOalkylaryl, --(CH.sub.2).sub.qOaryl, --(CH.sub.2).sub.qOaralkyl, --(CH.sub.2).sub.qOcycloalkyl, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHalkyl, --(CH.sub.2).sub.qN(alkyl).sub.2, --(CH.sub.2).sub.qNHalkylaryl, --(CH.sub.2).sub.qNHaryl, --(CH.sub.2).sub.qNHaralkyl, --(CH.sub.2).sub.qNHcycloalkyl, --(CH.sub.2).sub.qC(.dbd.O)NHalkyl, --(CH.sub.2).sub.qC(.dbd.O)N(alkyl).sub.2, --(CH.sub.2).sub.qC(.dbd.O)NHalkylaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaralkyl, --(CH.sub.2).sub.qC(.dbd.O)NHcycloalkyl, --(CH.sub.2).sub.qSO.sub.2alkyl, --(CH.sub.2).sub.qSO.sub.2alkylaryl, --(CH.sub.2).sub.qSO.sub.2aryl, --(CH.sub.2).sub.qSO.sub.2aralkyl, --(CH.sub.2).sub.qSO.sub.2cycloalkyl, --(CH.sub.2).sub.qNSO.sub.2alkyl, --(CH.sub.2).sub.qNSO.sub.2alkylaryl, --(CH.sub.2).sub.qNSO.sub.2aryl, --(CH.sub.2).sub.qNSO.sub.2aralkyl, --(CH.sub.2).sub.qNSO.sub.2cycloalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkylaryl, --(CH.sub.2).sub.qSO.sub.2NHaryl, --(CH.sub.2).sub.qSO.sub.2NHaralkyl, --(CH.sub.2).sub.qSO.sub.2NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl; m is 0 to 4; n is 0 to 4; each q can be the same or different, each being independently selected from 1 to 5; and r is 1 to 4; with the proviso that there are no two adjacent double bonds in any ring, and that when a nitrogen is substituted by two alkyl groups, said two alkyl groups may be optionally joined to each other to form a ring.

2. The compound according to claim 1, wherein ring G is a a dihydroimidazole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, dihydrothiazole, thiazole, triazole or tetrazole ring.

3. The compound according to claim 1, wherein Z is N.

4. The compound according to claim 1, wherein G is selected from the group consisting of: ##STR00259## ##STR00260## wherein a single bond or double bond.

5. The compound according to claim 1, wherein R.sup.3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, --N(R.sup.30).sub.2, --OR.sup.30 and --CF.sub.3.

6. The compound according to claim 5, wherein R.sup.3 is selected from the group consisting of H, --CH.sub.3, --CH.sub.2CH.sub.3, cyclopropyl, --F, --Cl, OCH.sub.3, OCF.sub.3 and CF.sub.3.

7. The compound according to claim 1, wherein R.sup.4 is selected from the group consisting of H, alkyl, halogen or CF.sub.3.

8. The compound according to claim 1, wherein R.sup.6 is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, --CN, --N(R.sup.30).sub.2, --OR.sup.30, --N.dbd.CH-alkyl, and --NR.sup.30C(.dbd.O)alkyl.

9. The compound according to claim 8, wherein R.sup.6 is selected from the group consisting of H, --NH.sub.2, --CH.sub.3, --CN and --F.

10. The compound according to claim 1, wherein R.sup.8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, or --(CH.sub.2).sub.qSO.sub.2NHR.sup.31.

11. The compound according to claim 1, wherein R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, --C(.dbd.O)N(H)R.sup.30, --C(.dbd.O)alkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --N(H)R.sup.30, --N(H)S(O.sub.2)R.sup.31, --N(H) C(.dbd.O)NH(R.sup.30), --OR.sup.30, --SO.sub.2(R.sup.31), and --SO.sub.2N(H)R.sup.30.

12. The compound according to claim 1, wherein the R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, cyclopropyl, --CF.sub.3, --CH.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)N(H)CH.sub.2CH.sub.2OH, --CH.sub.2N(H)C(.dbd.O)CF.sub.3, --C(.dbd.O)N(H)-cyclopropyl, --C(.dbd.O)N(H)CH.sub.2CF.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --N(H)CH.sub.2CH.sub.3, --N(H)CH(CH.sub.3).sub.2, --N(H)CH.sub.2CH.sub.2CH.sub.3, --N(H)CH.sub.2C(.dbd.O)OCH.sub.3, --N(H)CH.sub.2CH.sub.2OH, --N(H)CH.sub.2CH.sub.2NH.sub.2, --N(H)CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3, --N(H)CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --N(H)C(.dbd.O)N(H)CH.sub.2CH.sub.3, --N(H)CH.sub.2C(.dbd.O)NH.sub.2, --OCH.sub.3, .dbd.S and .dbd.O.

13. The compound according to claim 1, wherein R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, --CF.sub.3, --CH.sub.3, --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2NH.sub.2, --NH.sub.2, --NHCH.sub.3, --N(H)CH.sub.2CH.sub.3, --N(H)CH(CH.sub.3).sub.2, --N(H)CH.sub.2CH.sub.2CH.sub.3, --N(H)CH.sub.2C(.dbd.O)OCH.sub.3, and --N(H)CH.sub.2CH.sub.2OH.

14. The compound according to claim 1, wherein R.sup.10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl.

15. The compound according to claim 14, wherein R.sup.10 is selected from the group consisting of --CH.sub.3, --CH.sub.2CH.sub.3 and --CH.sub.2CH.sub.2CH.sub.3, and m is 0-2.

16. The compound according to claim 1, wherein R.sup.11 is selected from the group consisting of H, alkyl, hydroxyalkyl and carbonyl.

17. The compound according to claim 16, wherein R.sup.11 is H or --CH.sub.3.

18. The compound according to claim 1, wherein R.sup.12 is selected from the group consisting of H, CN, --C(.dbd.O)N(R.sup.30).sub.2 and alkyl.

19. The compound according to claim 18, wherein R.sup.12 is selected from the group consisting of H, --CH.sub.3, CN and --CH.sub.2CH.sub.3.

20. The compound according to claim 1, wherein the ring atoms of ring D are independently C or N and substituted by 0-4 R.sup.20 moieties.

21. The compound according to claim 1, wherein ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R.sup.20 moieties.

22. The compound according to claim 1, wherein the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylheteroaryl, alkylsulfinyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkoxy, aryl, aryloxy, cyano, cycloalkyl, cycloalkenyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxyalkyl, trifluromethyl, trifluoromethoxy, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)SO.sub.2N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, --SR.sup.30, --SO.sub.2N(R.sup.30).sub.2, --SO.sub.2(R.sup.31), --OSO.sub.2(R.sup.31), and --OSi(R.sup.30).sub.3.

23. The compound according to claim 1, wherein the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH.sub.3, CF.sub.3, OCF.sub.3, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31 , -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, and --OSO.sub.2(R.sup.31).

24. The compound according to claim 1, wherein two R.sup.20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0 to 4 R.sup.21 moieties.

25. The compound according to claim 1, wherein the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, --CN, --CH.sub.3, --CF.sub.3, --CH.sub.2OH, --CO.sub.2H, --CO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3, --OCF.sub.3, --OH, F, Cl, Br, --C(.dbd.NOH)NH.sub.2, --OCH.sub.2CH.sub.2S(O.sub.2)CH.sub.3, --C(.dbd.O)NH.sub.2, ##STR00261##

26. The compound according to claim 1, wherein Y is selected from the group consisting of: --(CHR.sup.13).sub.r--, --(CR.sup.13R.sup.13).sub.r--, --C(.dbd.O)-- and --CHR.sup.13C(.dbd.O)--.

27. The compound according to claim 1, wherein Y is selected from the group consisting of: --CH.sub.2--, --CH(CH.sub.3)--, --CH(CH.sub.2OH)--, --C(.dbd.O)-- and --CH(CO.sub.2alkyl)-.

28. The compound according to claim 1, wherein m is 0-2.

29. The compound according to claim 1, wherein n is 0-2.

30. The compound according to claim 1, wherein q is 1 or 2.

31. The compound according to claim 1, wherein r is 1 or 2.

32. The compound according to claim 1, wherein ring G is selected from the group consisting of: ##STR00262## ##STR00263## is a single bond or a double bond; R.sup.3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, --N(R.sup.30).sub.2, --OR.sup.30 and --CF.sub.3; R.sup.6 is selected from the group consisting of H, alkyl, halogen, hydroxyalkyl, --CN, --N(R.sup.30).sub.2, --OR.sup.30, --N.dbd.CH-alkyl, and --NR.sup.30C(.dbd.O)alkyl; R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, --C(.dbd.O)N(H)R.sup.30, --C(.dbd.O)alkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --N(H)R.sup.30, --N(H)S(O.sub.2)R.sup.31, --N(H)C(.dbd.O)NH(R.sup.30), --OR.sup.30, --SO.sub.2(R.sup.31), and --SO.sub.2N(H)R.sup.30; R.sup.10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl; R.sup.11 is selected from the group consisting of: H, alkyl, hydroxyalkyl, and carbonyl; R.sup.12 is selected from the group consisting of H, CN, --C(.dbd.O)N(R.sup.30).sub.2 and alkyl; ring D is a 5 to 6 membered aryl, heteroaryl, heterocyclenyl, or heterocyclyl ring and substituted by 0-4 R.sup.20 moieties; the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH.sub.3, CF.sub.3, OCF.sub.3, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, ##STR00264## Y is selected from the group consisting of: --CH.sub.2--, --CH(CH.sub.3)--, --CH(CH.sub.2OH)--, --C(.dbd.O)-- and --CH(CO.sub.2alkyl)-; m is 0-2; n is 0-2; q is 1 or 2; and r is 1 or 2.

33. the compound according to claim 1, selected from the group consisting of: TABLE-US-00002 Compound Number STRUCTURE 1 ##STR00265## 2 ##STR00266## 3 ##STR00267## 4 ##STR00268## 5 ##STR00269## 6 ##STR00270## 7 ##STR00271## 8 ##STR00272## 9 ##STR00273## 10 ##STR00274## 11 ##STR00275## 12 ##STR00276## 13 ##STR00277## 14 ##STR00278## 15 ##STR00279## 16 ##STR00280## 17 ##STR00281## 18 ##STR00282## 19 ##STR00283## 21 ##STR00284## 22 ##STR00285## 23 ##STR00286## 25 ##STR00287## 26 ##STR00288## 27 ##STR00289## 28 ##STR00290## 29 ##STR00291## 30 ##STR00292## 31 ##STR00293## 32 ##STR00294## 33 ##STR00295## 34 ##STR00296## 35 ##STR00297## 36 ##STR00298## 37 ##STR00299## 38 ##STR00300## 39 ##STR00301## 40 ##STR00302## 41 ##STR00303## 42 ##STR00304## 43 ##STR00305## 44 ##STR00306## 45 ##STR00307## 46 ##STR00308## 47 ##STR00309## 48 ##STR00310## 49 ##STR00311## 50 ##STR00312## 51 ##STR00313## 52 ##STR00314## 53 ##STR00315## 54 ##STR00316## 55 ##STR00317## 56 ##STR00318## 57 ##STR00319## 58 ##STR00320## 60 ##STR00321## 61 ##STR00322## 62 ##STR00323## 63 ##STR00324## 64 ##STR00325## 65 ##STR00326## 66 ##STR00327## 67 ##STR00328## 68 ##STR00329## 69 ##STR00330## 70 ##STR00331## 71 ##STR00332## 72 ##STR00333## 73 ##STR00334## 74 ##STR00335## 75 ##STR00336## 76 ##STR00337## 77 ##STR00338## 78 ##STR00339## 79 ##STR00340## 80 ##STR00341## 81 ##STR00342## 82 ##STR00343## 83 ##STR00344## 84 ##STR00345## 85 ##STR00346## 86 ##STR00347## 87 ##STR00348## 88 ##STR00349## 89 ##STR00350## 90 ##STR00351## 91 ##STR00352## 92 ##STR00353## 93 ##STR00354## 94 ##STR00355## 95 ##STR00356## 96 ##STR00357## 97 ##STR00358## 98 ##STR00359## 99 ##STR00360## 100 ##STR00361## 101 ##STR00362## 102 ##STR00363## 103 ##STR00364## 104 ##STR00365## 105 ##STR00366## 106 ##STR00367## 107 ##STR00368## 108 ##STR00369## 109 ##STR00370## 110 ##STR00371## 111 ##STR00372## 112 ##STR00373## 113 ##STR00374## 114 ##STR00375## 115 ##STR00376## 116 ##STR00377## 117 ##STR00378## 118 ##STR00379## 119 ##STR00380## 120 ##STR00381## 121 ##STR00382## 122 ##STR00383## 123 ##STR00384## 124 ##STR00385## 125 ##STR00386##

126 ##STR00387## 127 ##STR00388## 128 ##STR00389## 129 ##STR00390## 130 ##STR00391## 131 ##STR00392## 132 ##STR00393## 133 ##STR00394## 134 ##STR00395## 135 ##STR00396## 136 ##STR00397## 137 ##STR00398## 138 ##STR00399## 139 ##STR00400## 140 ##STR00401## 141 ##STR00402## 142 ##STR00403## 143 ##STR00404## 144 ##STR00405## 145 ##STR00406## 146 ##STR00407## 147 ##STR00408## 148 ##STR00409## 149 ##STR00410## 150 ##STR00411## 151 ##STR00412## 152 ##STR00413## 153 ##STR00414## 154 ##STR00415## 155 ##STR00416## 156 ##STR00417## 157 ##STR00418## 158 ##STR00419## 159 ##STR00420## 160 ##STR00421## 161 ##STR00422## 162 ##STR00423## 163 ##STR00424## 164 ##STR00425## 165 ##STR00426## 166 ##STR00427## 167 ##STR00428## 168 ##STR00429## 169 ##STR00430## 170 ##STR00431## 171 ##STR00432## 172 ##STR00433## 173 ##STR00434## 174 ##STR00435## 175 ##STR00436##

or a pharmaceutically acceptable salt, solvate or ester thereof.

34. The compound according to claim 1, wherein said compound is represented by structural Formula 2, Formula 3, Formula 4, Formula 5, Formula 6 or Formula 7: ##STR00437## ##STR00438## or a pharmaceutically acceptable salt, or ester thereof, wherein: the R.sup.8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.3 , --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, or --(CH.sub.2).sub.qSO.sub.2NHR.sup.31; the R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, arylalkyl, alkylaryl, cycloalkyl, heteroaryl, heterocyclenyl, heterocyclyl, --C(.dbd.O)N(H)R.sup.30, --C(.dbd.O)alkyl, --N(H)R.sup.30, --N(H)S(O.sub.2)R.sup.31, --N(H)C(.dbd.O)NH(R.sup.30), --OR.sup.30, --SO.sub.2(R.sup.31), .dbd.O, .dbd.S, and --SO.sub.2N(H)R.sup.30; L is C or N; in Formula 4 is a single bond or a double bond; and m, n, p, q, R.sup.10, R.sup.11, R.sup.12, R.sup.20 and Y are as defined in claim 1.

35. The compound according to claim 34, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, --N(R.sup.30).sub.2, --OR.sup.30 and --CF.sub.3.

36. The compound according to claim 34, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.6 is selected from the group consisting of H, alkyl, halogen, --N(R.sup.30).sub.2, --OR.sup.30 and --NR.sup.1C(.dbd.O)alkyl.

37. The compound according to claim 34, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.9 moieties are the same or different, each being independently selected from the group consisting of H, cyclopropyl, --CF.sub.3, --CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2OH, --CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3, --CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --C(.dbd.O)N(H)CH.sub.2CH.sub.2OH, --CH.sub.2N(H)C(.dbd.O)CF.sub.3, --C(.dbd.O)N(H)-cyclopropyl, --C(.dbd.O)N(H)CH.sub.2CF.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, --N(H)CH.sub.2CH.sub.3, --N(H)CH(CH.sub.3).sub.2, --N(H)CH.sub.2CH.sub.2CH.sub.3, --N(H)CH.sub.2C(.dbd.O)OCH.sub.3, --N(H)CH.sub.2CH.sub.2OH, --N(H)CH.sub.2CH.sub.2NH.sub.2, --N(H)CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3, --N(H)CH.sub.2CH.sub.2SO.sub.2CH.sub.3, --N(H)C(.dbd.O)N(H)CH.sub.2CH.sub.3, --N(H)CH.sub.2C(.dbd.O)NH.sub.2, .dbd.O, .dbd.S, and --OCH.sub.3.

38. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl, and carbonyl.

39. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.11 is selected from the group consisting of: H, alkyl and carbonyl.

40. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.12 is selected from the group consisting of H, --CH.sub.3, CN or --CH.sub.2CH.sub.3.

41. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH.sub.3, CF.sub.3, OCF.sub.3, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31 , -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, --OSO.sub.2(R.sup.31), ##STR00439##

42. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, --CN, --CH.sub.3, --CF.sub.3, --CH.sub.2OH, --CO.sub.2H, --CO.sub.2CH.sub.3, --NH.sub.2, --NHCH.sub.3, --OCF.sub.3, --OH, F, Cl, Br, --C(.dbd.NOH)NH.sub.2, --OCH.sub.2CH.sub.2S(O.sub.2)CH.sub.3, --C(.dbd.O)NH.sub.2, ##STR00440##

43. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, L is carbon.

44. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, L is nitrogen.

45. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, Y is selected from the group consisting of: --CH.sub.2--, --C(.dbd.O)--, --CH(CH.sub.2OH)-- and --CH(CO.sub.2alkyl)-.

46. The compound according to claim 35, wherein in Formulas 2, 3, 4, 5, 6 and 7, R.sup.3 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl, halogen, --N(R.sup.30).sub.2, --OR.sup.30 and --CF.sub.3; R.sup.6 is selected from the group consisting of H, alkyl, halogen, --N(R.sup.30).sub.2, --OR.sup.30, and --NR.sup.1C(.dbd.O)alkyl; the R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, --C(.dbd.O)N(H)R.sup.30, --C(.dbd.O)alkyl, --N(H)R.sup.30, --N(H)S(O.sub.2)R.sup.31, --N(H)C(.dbd.O)NH(R.sup.30), --OR.sup.30, --SO.sub.2(R.sup.31), and --SO.sub.2N(H)R.sup.30; R.sup.10 is selected from the group consisting of H, alkyl, aralkyl, hydroxyalkyl and carbonyl; the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, amino, halogen, CN, CH.sub.3, CF.sub.3, OCF.sub.3, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, and --OSO.sub.2(R.sup.31), ##STR00441## Y is selected from the group consisting of: --CH.sub.2--, --C(.dbd.O)--, --CH(CH.sub.2OH)-- and --CH(CO.sub.2alkyl)-; m is 0-2; q is 1 or 2; and r is 1 or 2.

47. A compound according to claim 1, selected from the group consisting of the following: ##STR00442## ##STR00443## or a pharmaceutically acceptable salt, or ester thereof.

48. A compound according to claim 1, selected from the group consisting of the following: ##STR00444## or a pharmaceutically acceptable salt, or ester thereof.

49. A compound having the structural formula selected from the group consisting of the following: ##STR00445## or a pharmaceutically acceptable salt, or ester thereof.

50. A compound according to claim 1 in purified form.

Description

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic substituted piperazines with CXCR3 antagonist activity, pharmaceutical compositions containing one or more such antagonists, one or more such antagonists in combination with other compounds with chemokine activity, one or more such antagonists in combination with known immunosuppressive agents, non-limiting example(s) include Methotrexate, interferon, cyclosporin, FK-506 and FTY720, methods of preparing such antagonists and methods of using such antagonists to modulate CXCR3 activity. This invention also discloses methods of using such CXCR3 antagonists for the treatment (non-limiting examples include palliative, curative and prophylactic therapies) of diseases and conditions where CXCR3 has been implicated. Diseases and conditions where CXCR3 has been implicated include but are not limited to inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune disease (multiple sclerosis, rheumatoid arthritis), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, type I diabetes, viral meningitis and tuberculoid leprosy. CXCR3 antagonist activity has also been indicated as a therapy for tumor growth suppression as well as graft rejection (allograft and zenograft rejections for example).

BACKGROUND OF THE INVENTION

Chemokines constitute a family of cytokines that are produced in inflammation and regulate leukocyte recruitment (Baggiolini, M. et al., Adv. Immunol., 55: 97-179 (1994); Springer, T. A., Annual Rev. Physio., 57: 827-872 (1995); and Schall, T. J. and K. B. Bacon, Curr. Opin. Immunol, 6: 865-873 (1994)). Chemokines are capable of selectively inducing chemotaxis of the formed elements of the blood (other than red blood cells), including leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes, such as T cells and B cells. In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca.sup.2+].sub.i), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.

Chemokines are related in primary structure and share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine motif, the family can be divided into distinct branches, including the C--X--C chemokines (.alpha.-chemokines) in which the first two conserved cysteines are separated by an intervening residue (e.g., IL-8, IP-10, Mig, I-TAC, PF4, ENA-78, GCP-2, GRO.alpha., GRO.beta., GRO.delta., NAP-2, NAP-4), and the C--C chemokines (.beta.-chemokines), in which the first two conserved cysteines are adjacent residues (e.g., MIP-1.alpha., MIP-1.beta., RANTES, MCP-1, MCP-2, MCP-3, I-309) (Baggiolini, M. and Dahinden, C. A., Immunology Today, 15: 127-133 (1994)). Most CXC-chemokines attract neutrophil leukocytes. For example, the CXC-chemokines interleukin-8 (IL-8), GRO alpha (GRO.alpha.), and neutrophil-activating peptide 2 (NAP-2) are potent chemoattractants and activators of neutrophils. The CXC-chemokines designated Mig (monokine induced by gamma interferon) and IP-10 (interferon-gamma inducible 10 kDa protein) are particularly active in inducing chemotaxis of activated peripheral blood lymphocytes.

CC-chemokines are generally less selective and can attract a variety of leukocyte cell types, including monocytes, eosinophils, basophils, T lymphocytes and natural killer cells. CC-chemokines such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), and the macrophage inflammatory proteins 1.alpha. and 1.beta. (MIP-1.alpha. and MIP-1.beta.) have been characterized as chemoattractants and activators of monocytes or lymphocytes, but do not appear to be chemoattractants for neutrophils.

A chemokine receptor that binds the CXC-chemokines IP-10 and Mig has been cloned, characterized (Loetscher, M. et al., J. Exp. Med., 184: 963-969 (1996)) and designated CXCR3. CXCR3 is a G-protein coupled receptor with seven transmembrane-spanning domains and has been shown to be restrictively expressed in activated T cells, preferentially human Th1 cells. On binding of the appropriate ligand, chemokine receptors transduce an intracellular signal through the associated G-protein resulting in a rapid increase in intracellular calcium concentration.

The CXCR3 receptor mediates Ca.sup.2+ (calcium ion) mobilization and chemotaxis in response to IP-10 and Mig. CXCR3 expressing cells show no significant response to the CXC-chemokines IL-8, GRO.alpha., NAP-2, GCP-2 (granulocyte chemotactic protein-2), ENA78 (epithelial-derived neutrophil-activating peptide 78), PF4 (platelet factor 4), or the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-I.alpha., MIP-1.beta., RANTES, 1309, eotaxin or lymphotactin. Moreover, a third ligand for CXCR3, I-TAC (Interferon-inducible T cell Alpha Chemoattractant), has also been found to bind to the receptor with high affinity and mediate functional responses (Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)).

The restricted expression of human CXCR3 in activated T lymphocytes and the ligand selectivity of CXCR3 are noteworthy. The human receptor is highly expressed in IL-2 activated T lymphocytes, but was not detected in resting T lymphocytes, monocytes or granulocytes (Qin, S. et al., J. Clin. Invest., 101: 746-754 (1998)). Additional studies of receptor distribution indicate that it is mostly CD3.sup.+ cells that express CXCR3, including cells which are CD95.sup.+, CD45RO.sup.30, and CD45RA.sup.low, a phenotype consistent with previous activation, although a proportion of CD20.sup.+ (B) cells and CD56.sup.+ (NK) cells also express this receptor. The selective expression in activated T lymphocytes is of interest, because other receptors for chemokines which have been reported to attract lymphocytes (e.g., MCP-1, MCP-2, MCP-3, MIP-1.alpha., MIP-1.beta., RANTES) are also expressed by granulocytes, such as neutrophils, eosinophils, and basophils, as well as monocytes. These results suggest that the CXCR3 receptor is involved in the selective recruitment of effector T cells.

CXCR3 recognizes unusual CXC-chemokines, designated IP-10, Mig and I-TAC. Although these belong to the CXC-subfamily, in contrast to IL-8 and other CXC-chemokines which are potent chemoattractants for neutrophils, the primary targets of IP-10, Mig and I-TAC are lymphocytes, particularly effector cells such as activated or stimulated T lymphocytes and natural killer (NK) cells (Taub, D. D. et al., J Exp. Med., 177: 18090-1814 (1993); Taub, D. D. et al., J. Immunol., 155: 3877-3888 (1995); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)). (NK cells are large granular lymphocytes, which lack a specific T cell receptor for antigen recognition, but possess cytolytic activity against cells such as tumor cells and virally infected cells.) Consistently, IP-10, Mig and I-TAC lack the ELR motif, an essential binding epitope in those CXC-chemokines that efficiently induce neutrophil chemotaxis (Clark-Lewis, I. et al., J. Biol. Chem. 266: 23128-23134 (1991); Hebert, C. A. et al., J. Biol. Chem., 266: 18989-18994 (1991); and Clark-Lewis, 1. et al., Proc. Natl. Acad. Sci. USA, 90: 3574-3577 (1993)). In addition, both recombinant human Mig and recombinant human IP-10 have been reported to induce calcium flux in tumor infiltrating lymphocytes (TIL) (Liao, F. et al., J Exp. Med, 182: 1301-1314 (1995)). While IP-10 has been reported to induce chemotaxis of monocytes in vitro (Taub, D. D. et al., J. Exp. Med., 177: 1809-1814 (1993), the receptor responsible has not been identified), human Mig and I-TAC appear highly selective, and do not show such an effect (Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)). IP-10 expression is induced in a variety of tissues in inflammatory conditions such as psoriasis, fixed drug eruptions, cutaneous delayed-type hypersensitivity responses and tuberculoid leprosy as well as tumors and in animal model studies, for example, experimental glomerulonephritis, and experimental allergic encephalomyelitis. IP-10 has a potent in vivo antitumor effect that is T cell dependent, is reported to be an inhibitor of angiogenesis in vivo and can induce chemotaxis and degranulation of NK cells in vitro, suggesting a role as a mediator of NK cell recruitment and degranulation (in tumor cell destruction, for example) (Luster, A. D. and P. Leder, J. Exp. Med., 178: 1057-1065 (1993); Luster, A. D. et al., J Exp. Med. 182: 219-231 (1995); Angiolillo, A. L. et al., J. Exp. Med., 182: 155-162 (1995); Taub, D. D. et al., J. Immunol., 155: 3877-3888 (1995)). The expression patterns of IP-10, Mig and I-TAC are also distinct from that of other CXC chemokines in that expression of each is induced by interferon-gamma (IFN.delta.), while the expression of IL-8 is down-regulated by IFN.delta. (Luster, A. D. et al., Nature, 315: 672-676 (1985); Farber, J. M., Proc. Natl. Acad. Sci. USA, 87: 5238-5242 (1990); Farber, J. M., Biochem. Biophys. Res. Commun., 192 (1): 223-230 (1993), Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995); Seitz, M. et al., J. Clin. Invest., 87: 463-469 (1991); Galy, A. H. M. and H. Spits, J. Immunol., 147: 3823-3830 (1991); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)).

Chemokines are recognized as the long-sought mediators for the recruitment of lymphocytes. Several CC-chemokines were found to elicit lymphocyte chemotaxis (Loetscher, P. et al., FASEB J., 8: 1055-1060 (1994)), however, they are also active on granulocytes and monocytes (Uguccioni, M. et al., Eur. J. Immunol., 25: 64-68 (1995); Baggiolini, M. and C. A. Dahinden, Immunol. Today, 15: 127-133 (1994)). The situation is different for IP-10, Mig and I-TAC, which are selective in their action on lymphocytes, including activated T lymphocytes and NK cells, and which bind CXCR3, a receptor which does not recognize numerous other chemokines and which displays a selective pattern of expression.

In view of these observations, it is reasonable to conclude that the formation of the characteristic infiltrates in inflammatory lesions, such as, for example, delayed-type hypersensitivity lesions, sites of viral infection and certain tumors is a process mediated via CXCR3 and regulated by CXCR3 expression. Lymphocytes, particularly T lymphocytes, bearing a CXCR3 receptor as a result of activation can be recruited into inflammatory lesions, sites of infection and/or tumors by IP-10, Mig and/or I-TAC, which can be induced locally by interferon-gamma. Thus, CXCR3 plays a role in the selective recruitment of lymphocytes, particularly effector cells such as activated or stimulated T lymphocytes. Accordingly, activated and effector T cells have been implicated in a number of disease states such as graft-rejection, inflammation, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and psoriasis. Thus, CXCR3 represents a promising target for the development of novel therapeutics.

Reference is made to PCT Publication No. WO 93/10091 (Applicant: Glaxo Group Limited, Published May 27, 1993) which discloses piperidine acetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation having the formula:

##STR00002##

An illustrative compound of that series is:

##STR00003##

Reference is also made to PCT Publication No. WO 99/20606 (Applicant: J. Uriach & CIA. S. A., Published Apr. 29, 1999) which discloses piperazines as platelet aggregation inhibitors having the formula:

##STR00004##

Reference is also made to U.S. Patent Application No. US 2002/0018776 A1 (Applicant: Hancock, et al. Published Feb. 14, 2002) which discloses methods of treating graft rejection.

Reference is also made to PCT Publication No. WO 03/098185 A2 (Applicant: Renovar, Inc., Published Nov. 27, 2003) which discloses methods of diagnosing and predicting organ transplant rejection by detection of chemokines, for example, CXCR3 and CCL chemokines in urine.

Reference is also made to PCT Publication No. WO 03/082335 A1 (Applicant: Sumitomo Pharmaceuticals Co. Ltd., Published Oct. 9, 2003) which discloses methods of screening a CXCR3 ligand and methods of diagnosing type 2 diabetes by detecting the expression dose of a CXCR3 ligand in a biological sample.

Reference is also made to PCT Publication No. WO 02/085861 (Applicant: Millennium Pharmaceuticals, Inc. Published Oct. 31, 2002) which discloses imidazolidine compounds and their use as CXCR3 antagonists having the formula:

##STR00005##

An illustrative compound of that series is:

##STR00006##

Reference is also made to PCT Publication No. WO 03/101970 (Applicant: Smithkline Beecham Corporation, Published Dec. 11, 2003) which discloses imidazolium compounds and their use as CXCR3 antagonists having the formula:

##STR00007##

An illustrative example of that series is:

##STR00008##

Reference is also made to U.S. Patent Application No. US 2003/0055054 A1 (Applicant: Medina et al, Published Mar. 20, 2003) and related patent U.S. Pat. No. 6 794 379 B2 ((Applicant: Medina et al, Published Sep. 21, 2004) which discloses compounds with CXCR3 activity having the formula:

##STR00009##

An illustrative compound of that series is:

##STR00010##

Reference is also made to U.S. Pat. No. 6,124,319 (Applicant: MacCoss et al., issued Sep. 6, 2000) which discloses compounds useful as chemokine receptor modulators having the formula:

##STR00011##

Reference is also made to PCT Publication WO 03/070242 A1 (Applicant: CELLTECH R& D limited, Published Aug. 28, 2003) which discloses compounds useful as "chemokine receptor inhibitors for the treatment of inflammatory diseases" having the formula:

##STR00012##

Reference is also made to PCT Publication WO 04/074287 A1, WO 04/074273 A1, WO 04/74278 (Applicant: AstraZeneca R & D Published February 19.sup.th 2004) which discloses pyridine derivatives, processes for their preparation and use in the modulation of autoimmune disease, having the formula:

##STR00013## where R3 is phenyl, or a 5- or 6-membered aromatic ring with 1 or more nitrogen atoms.

There is a need for compounds that are capable of modulating CXCR3 activity. For example, there is a need for new treatments and therapies for diseases and conditions associated with CXCR3 such as inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune disease (multiple sclerosis, rheumatoid arthritis) and graft rejection (allograft and zenograft rejections for example) as well as infectious diseases, cancers and tumors, fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, type I diabetes, viral meningitis and tuberculoid leprosy.

There is a need for methods of treatment or prevention or amelioration of one or more symptoms of diseases and conditions associated with CXCR3. There is a need for methods for modulating CXCR3 activity using the compounds provided herein.

SUMMARY OF THE INVENTION

In its many embodiments, the invention provides novel compounds of the Formula 1:

##STR00014## or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:

Z is N, NO, NOH or C(R.sup.29);

G represents a 5-membered heteroaryl or heterocyclenyl ring containing at least one --C.dbd.N-- moiety as part of said heteroaryl or heterocyclenyl ring, said heteroaryl or heterocyclenyl ring optionally additionally containing on the ring (i.e., as ring moieties) one or more moieties which can be the same or different, each being independently selected from the group consisting of N,N(.fwdarw.O), O, S, S(O) and S(O.sub.2), further wherein said heteroaryl or heterocyclenyl ring can be either (i) unsubstituted, or (ii) optionally independently substituted on one or more ring carbon atoms with one or more R.sup.9 substituents, or on one or more ring nitrogen atoms with one or more R.sup.8 substituents, wherein said R.sup.8 and R.sup.9 substituents can be the same or different;

R.sup.3, R.sup.4, R.sup.6 and R.sup.29 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, --CN, CF.sub.3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, --N.dbd.CH--(R.sup.31), --C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30).sub.2, --OR.sup.30, --SO.sub.2(R.sup.31), --N(R.sup.30)C(.dbd.O)N(R .sup.30).sub.2 and --N(R.sup.30)C(.dbd.O)R.sup.31;

the R.sup.8 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)OR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, or --(CH.sub.2).sub.qSO.sub.2NHR.sup.31;

the R.sup.9 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, alkoxy, amidinyl, aryl, cycloalkyl, cyano, heteroaryl, heterocyclyl, hydroxyl, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.S)N(R.sup.30).sub.2, --C(.dbd.O)alkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, --N(R.sup.30).sub.2, --N(R.sup.30)S(O.sub.2)R.sup.31, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --OR.sup.30, --SO.sub.2(R.sup.31), --SO.sub.2N(R.sup.30).sub.2, .dbd.O and .dbd.S;

the R.sup.10 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, heterocyclyl, alkylaryl, arylalkyl, --CO.sub.2H, hydroxyalkyl, --C(.dbd.O)N(R.sup.30).sub.2, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --OR.sup.30, halogen, .dbd.O, and --C(.dbd.O)R.sup.31;

the R.sup.11 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, alkylaryl, arylalkyl, carboxamide, CO.sub.2H, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --OR.sup.30, halogen, .dbd.O, and --C(.dbd.O)R.sup.31;

R.sup.12 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, --CN, --C(.dbd.O)N(R.sup.30).sub.2, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31 and --S(O.sub.2)R.sup.31;

ring D is a five to nine membered cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl ring having 0-4 heteroatoms independently selected from O, S or N, wherein ring D is unsubstituted or optionally substituted with 1-5 independently selected R.sup.20 moieties;

the R.sup.20 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, --alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.NR.sup.30)NHR.sup.30, --C(.dbd.NOH)N(R.sup.30).sub.2, --C(.dbd.NOR.sup.31)N(R.sup.30).sub.2, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)S(O).sub.2N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, --SR.sup.30, --SO.sub.2N(R.sup.30).sub.2, --SO.sub.2(R.sup.31), --OSO.sub.2(R.sup.31), and --OSi(R.sup.30).sub.3; or alternatively two R.sup.20 moieties are linked together to form a five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring wherein said five or six membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl ring is fused to ring D and the fused ring is optionally substituted with 0-4 R.sup.21 moieties;

the R.sup.21 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOR.sup.31, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, -alkynylC(R.sup.31).sub.2OR.sup.31, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --C(.dbd.NR.sup.30)NHR.sup.30, --C(.dbd.NOH)N(R.sup.30).sub.2, --C(.dbd.NOR.sup.31)N(R.sup.30).sub.2, --C(.dbd.O)OR.sup.30, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)R.sup.31, --NHC(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)OR.sup.31, --N(R.sup.30)C(.dbd.NCN)N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --N(R.sup.30)S(O).sub.2N(R.sup.30).sub.2, --OR.sup.30, --OC(.dbd.O)N(R.sup.30).sub.2, --SR.sup.+, --SO.sub.2N(R.sup.30).sub.2, --SO.sub.2(R.sup.31), --OSO.sub.2(R.sup.31), and --OSi(R.sup.30).sub.3;

Y is selected from the group consisting of --(CR.sup.13R.sup.13).sub.r--, --CHR.sup.13C(.dbd.O)--, --(CHR.sup.13).sub.rO--, --(CHR.sup.13).sub.r N(R.sup.30)--, --C(.dbd.O)--, --C(.dbd.NR.sup.30)--, --C(.dbd.N--OR.sup.30)--, --CH(C(.dbd.O)NHR.sup.30)--, CH-heteroaryl-, --C(R.sup.13R.sup.13).sub.rC(R.sup.13).dbd.C(R.sup.13)--, --(CHR.sup.13).sub.rC(.dbd.O)-- and --(CHR.sup.13).sub.rN(H)C(.dbd.O)--; or alternatively Y is cycloalkyl, heterocyclenyl, or heterocyclyl wherein the cycloalkyl, heterocyclenyl, or heterocyclyl is fused with ring D;

the R.sup.13 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclenyl, heterocyclyl, spiroalkyl, --CN, --CO.sub.2H, --C(.dbd.O)R.sup.30, --C(.dbd.O)N(R.sup.30).sub.2, --(CHR.sup.30).sub.qOH, --(CHR.sup.30).sub.qOR.sup.31, --(CHR.sup.30).sub.qNH.sub.2, --(CHR.sup.30).sub.qNHR.sup.31, --(CH.sub.2).sub.qC(.dbd.O)NHR.sup.31, --(CH.sub.2).sub.qSO.sub.2R.sup.31, --(CH.sub.2).sub.qNSO.sub.2R.sup.31, --(CH.sub.2).sub.qSO.sub.2NHR.sup.31, --NH.sub.2, --N(R.sup.30).sub.2, --N(R.sup.30)C(.dbd.O)N(R.sup.30).sub.2, --N(R.sup.30)SO.sub.2(R.sup.31), --OH, OR.sup.30, --SO.sub.2N(R.sup.30).sub.2, and --SO.sub.2(R.sup.31);

the R.sup.30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOalkyl, --(CH.sub.2).sub.qOalkylaryl, --(CH.sub.2).sub.qOaryl, --(CH.sub.2).sub.qOaralkyl, --(CH.sub.2).sub.qOcycloalkyl, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHalkyl, --(CH.sub.2).sub.qN(alkyl).sub.2, --(CH.sub.2).sub.qNHalkylaryl, --(CH.sub.2).sub.qNHaryl, --(CH.sub.2).sub.qNHaralkyl, --(CH.sub.2).sub.qNHcycloalkyl, --(CH.sub.2).sub.qC(.dbd.O)NHalkyl, --(CH.sub.2).sub.qC(.dbd.O)N(alkyl).sub.2, --(CH.sub.2).sub.qC(.dbd.O)NHalkylaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaralkyl, --(CH.sub.2).sub.qC(.dbd.O)NHcycloalkyl, --(CH.sub.2).sub.qSO.sub.2alkyl, --(CH.sub.2).sub.qSO.sub.2alkylaryl, --(CH.sub.2).sub.qSO.sub.2aryl, --(CH.sub.2).sub.qSO.sub.2aralkyl, --(CH.sub.2).sub.qSO.sub.2cycloalkyl, --(CH.sub.2).sub.qNSO.sub.2alkyl, --(CH.sub.2).sub.qNSO.sub.2alkylaryl, --(CH.sub.2).sub.qNSO.sub.2aryl, --(CH.sub.2).sub.qNSO.sub.2aralkyl, --(CH.sub.2).sub.qNSO.sub.2cycloalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkylaryl, --(CH.sub.2).sub.qSO.sub.2NHaryl, --(CH.sub.2).sub.qSO.sub.2NHaralkyl, --(CH.sub.2).sub.qSO.sub.2NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;

the R.sup.31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, --(CH.sub.2).sub.qOH, --(CH.sub.2).sub.qOalkyl, --(CH.sub.2).sub.qOalkylaryl, --(CH.sub.2).sub.qOaryl, --(CH.sub.2).sub.qOaralkyl, --(CH.sub.2).sub.qOcycloalkyl, --(CH.sub.2).sub.qNH.sub.2, --(CH.sub.2).sub.qNHalkyl, --(CH.sub.2).sub.qN(alkyl).sub.2, --(CH.sub.2).sub.qNHalkylaryl, --(CH.sub.2).sub.qNHaryl, --(CH.sub.2).sub.qNHaralkyl, --(CH.sub.2).sub.qNHcycloalkyl, --(CH.sub.2).sub.qC(.dbd.O)NHalkyl, --(CH.sub.2).sub.qC(.dbd.O)N(alkyl).sub.2, --(CH.sub.2).sub.qC(.dbd.O)NHalkylaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaryl, --(CH.sub.2).sub.qC(.dbd.O)NHaralkyl, --(CH.sub.2).sub.qC(.dbd.O)NHcycloalkyl, --(CH.sub.2).sub.qSO.sub.2alkyl, --(CH.sub.2).sub.qSO.sub.2alkylaryl, --(CH.sub.2).sub.qSO.sub.2aryl, --(CH.sub.2).sub.qSO.sub.2aralkyl, --(CH.sub.2).sub.qSO.sub.2cycloalkyl, --(CH.sub.2).sub.qNSO.sub.2alkyl, --(CH.sub.2).sub.qNSO.sub.2alkylaryl, --(CH.sub.2).sub.qNSO.sub.2aryl, --(CH.sub.2).sub.qNSO.sub.2aralkyl, --(CH.sub.2).sub.qNSO.sub.2cycloalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkyl, --(CH.sub.2).sub.qSO.sub.2NHalkylaryl, --(CH.sub.2).sub.qSO.sub.2NHaryl, --(CH.sub.2).sub.qSO.sub.2NHaralkyl, --(CH.sub.2).sub.qSO.sub.2NHcycloalkyl, heterocyclenyl, heterocyclyl, and hetroaryl;

m is 0 to 4