A method of inhibiting or blocking T-cell mediated chemotaxis or treating a disease selected from the group consisting of inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, tuberculoid leprosy, ophthalmic inflammation or dry eye, type I diabetes, viral meningitis and cancer, in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound having the structure shown in Formula 1
- or a pharmaceutically acceptable salt thereof, wherein:
- Z is N, NO, or NOH;
- G represents a 5-membered heteroaryl or heterocyclenyl ring containing at least one —C═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(→O), O, S, S(O) and S(O2), 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 R9 substituents, or on one or more ring nitrogen atoms with one or more R8 substituents, wherein said R8 and R9 substituents can be the same or different;
- R3, R4, R6 and R29 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aralkyl, —CN, CF3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, —N═CH—(R31), —C(═O)N(R30)2, —N(R30)2, —OR30, —SO2(R31), —N(R30)C(═O)N(R30)2 and —N(R30)C(═O)R31;
- the R8 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, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31—(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNSO2R31, —(CH2)qC(═O)OR31, and —(CH2)qSO2NHR31;
- the R9 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(═O)N(R30)2, —C(═S)N(R30)2, —C(═O)alkyl, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, (CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNSO2R3, —(CH2)qSO2NHR31, —N(R30)2, —N(R30)S(O2)R31, —N(R30)C(═O)N(R30)2, —OR30, —SO2(R31), —SO2N(R30)2, ═O and ═S;
- the R10 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, —CO2H, hydroxyalkyl, —C(═O)N(R30)2, —(CH2)qOH, —(CH2)qOR31—OR30, halogen, ═O, and —C(═O)R31;
- the R12 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, CO2H, —(CH2)qOH, —(CH2)qOR31, —OR30, halogen, ═O, and —C(═O)R31;
- R12 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, —CN, —C(═O)N(R30)2, —(CH2)qOH, —(CH2)qOR31 and —S(O2)R31;
- 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 R20 moieties;
- the R20 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, —(CH2)qOH, —(CH2)qOR31—(CH2)qNH2, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R30(CH2)qNSO2R31, —(CH2)qSO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)N(R3)2, —C(═NR30)NHR30—C(═NOH)N(R30)2, —C(═NOR31)N(R30)2, —C(═O)OR30, —N(R3)2, —N(R30)C(═O)R31, —NHC(═O)N(R30)2, —N(R30)C(═O)OR31—N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)SO2(R31), —N(R30)C(═O)N(R30)2, —N(R30)SO2(R31), —N(R30)S(O)2N(R30)2, —OR30, —OC(═O)N(R30)2, —SR30, —SO2N(R30)2, —SO2(R31), —OSO2(R31), and —OSi(R30)3;
- or alternatively two R20 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 R21 moieties;
- the R21 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, —(CH2)qOH, —(CH2)qOR31, —(CH2)qNH2, —(CH2)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNSO2R31, —(CH2)qSO2NHR31, -alkynylC(R31)2OR31, —C(═O)R30, —C(═O)N(R30)2, —C(═NR30)NHR30C(═NOH)N(R30)2, —C(═NOR31)N(R30)2, —C(═O)OR30, —N(R30)2, —N(R30)C(═O)R31—NHC(═O)N(R30)2, —N(R30)C(═O)OR31, —N(R30)C(═NCN)N(R30)2, —N(R30)C(═O)N(R30)SO2(R31), —N(R30)C(═O)N(R30)2, —N(R30)SO2(R31), —N(R30)S(O)2N(R30)2, —OR30, —OC(═O)N(R30)2, —SR30, —SO2N(R30)2—SO2(R31), —OSO2(R31), and —OSi(R30)3;
- Y is selected from the group consisting of —(CR12R13)r—, —CHR13C(═O)—, —(CHR13)nO—, —(CHR13)rN(R30)—, —C(═O)—, —C(═NR30)—, —C(═N—OR30)—, —CH(C(═O)NHR30)—, CH-heteroaryl-, —C(R13R13)rC(R13)═C(R13)—, —(CHR13)rC(═O)— and —(CHR13)rN(H)C(═O)—;
- or alternatively Y is cycloalkyl, heterocyclenyl, or heterocyclyl wherein the cycloalkyl, heterocyclenyl, or heterocyclyl is fused with ring D;
- the R13 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, —CO2H, —C(═O)R30, —C(═O)N(R30)2, —(CHR30)qOH, —(CHR30)qOR31, —(CHR30)qNH2, —(CHR30)qNHR31, —(CH2)qC(═O)NHR31, —(CH2)qSO2R31, —(CH2)qNSO2R31, —(CH2)qSO2NHR31—NH2, —N(R30)2, —N(R30)C(═O)N(R30)2, —N(R30)SO2(R31), —OH, OR30, —SO2N(R30)2, and —SO2(R31);
- the R30 moieties can be the same or different, each being independently selected from the group consisting of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, CN, —(CH2)qOH, —(CH2)qOalkyl, —(CH2)qOalkylaryl, —(CH2)qOaryl, —(CH2)qOaralkyl, —(CH2)qOcycloalkyl, —(CH2)qNH2, —(CH2)qNHalkyl, —(CH2)qN(alkyl)2, —(CH2)qNHalkylaryl, —(CH2)qNHaryl, —(CH2)qNHaralkyl, —(CH2)qNHcycloalkyl, —(CH2)qC(═O)NHalkyl, —(CH2)qC(═O)N(alkyl)2, —(CH2)qC(═O)N Halkylaryl, —(CH2)qC(═O)NHaryl, —(CH2)qC(═O)N Haralkyl, —(CH2)qC(═O)NHcycloalkyl, —(CH2)qSO2alkyl, —(CH2)qSO2alkylaryl, —(CH2)qSO2aryl, —(CH2)qSO2aralkyl, —(CH2)qSO2cycloalkyl, —(CH2)qNSO2alkyl, —(CH2)qNSO2alkylaryl, —(CH2)qNSO2aryl, —(CH2)qNSO2aralkyl, —(CH2)qNSO2cycloalkyl, —(CH2)qSO2NHalkyl, —(CH2)qSO2NHalkylaryl, —(CH2)qSO2NHaryl, —(CH2)qSO2NHaralkyl, —(CH2)qSO2NHcycloalkyl, heterocyclenyl, heterocyclyl, and heteroaryl;
- the R31 moieties can be the same or different, each being independently selected from the group consisting of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, —(CH2)qOH, —(CH2)qOalkyl, —(CH2)qOalkylaryl, —(CH2)qOaryl, —(CH2)qOaralkyl, —(CH2)qOcycloalkyl, —(CH2)qNH2, —(CH2)qNHalkyl, —(CH2)qN(alkyl)2, —(CH2)qNHalkylaryl, —(CH2)qNHaryl, —(CH2)qNHaralkyl, —(CH2)qN Hcycloalkyl, —(CH2)qC(═O)N Halkyl, —(CH2)qC(═O)N(alkyl)2, —(CH2)qC(═O)N Halkylaryl, —(CH2)qC(═O)NHaryl, —(CH2)qC(═O)NHaralkyl, —(CH2)qC(═O)NHcycloalkyl, —(CH2)qSO2alkyl, —(CH2)qSO2alkylaryl, —(CH2)qSO2aryl, —(CH2)qSO2aralkyl, —(CH2)qSO2cycloalkyl, —(CH2)qNSO2alkyl, —(CH2)qNSO2alkylaryl, —(CH2)qNSO2aryl, —(CH2)qNSO2aralkyl, —(CH2)qNSO2cycloalkyl, —(CH2)qSO2N Halkyl, —(CH2)qSO2NHalkylaryl, —(CH2)qSO2NHaryl, —(CH2)qSO2NHaralkyl, —(CH2)qSO2NHcycloalkyl, 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.