主权项 |
1. A method of disrupting leukocyte function comprising contacting leukocytes with a compound having a structure wherein A is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic; X is selected from the group consisting of C(Rb)2, CH2CHRb, and CH═C(Rb); Y is selected from the group consisting of null, S, SO, SO2, NH, O, C(═O), OC(═O), C(═O)O, and NHC(═O)CH2S; R1 and R2, independently, are selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, halo, NHC(═O)C1-3alkyleneN(Ra)2, NO2, ORa, CF3, OCF3, N(Ra)2, CN, OC(═O)Ra, C(═O)Ra, C(═O)ORa, arylORb, Het, NRaC(═O)C1-3alkyleneC(═O)Ra, arylOC1-3-alkyleneN(Ra)2, arylOC(═O)Ra, C1-4alkyleneC(═O)ORa, OC1-4alkyleneC(═O)ORa, C1-4alkyleneOC1-4alkyleneC(═O)ORa, C(═O)NRaSO2Ra, C1-4alkyleneN(Ra)2, C2-6alkenyleneN(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, OC2-4-alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2alkyleneORa, OC2-4alkyleneNRaC(═O)ORa, NRaC1-4alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-4alkyl)2, NRa(SO2C1-4alkyl), SO2N(Ra)2, OSO2CF3, C1-3alkylenearyl, C1-4alkyleneHet, C1-6alkyleneORb, C1-3alkyleneN(Ra)2, C(═O)N(Ra)2, NHC(═O)C1-C3alkylenearyl, C3-8cycloalkyl, C3-8heterocycloalkyl, arylOC1-3-alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8-heterocycloalkyl, NHC(═O)C1-3alkyleneHet, OC1-4alkyleneOC1-4alkyleneC(═O)ORb, C(═O)C1-4alkyleneHet, and NHC(═O)haloC1-6alkyl; or R1 and R2 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom; R3 is selected from the group consisting of optionally substituted hydrogen, C1-8alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-4alkylenecycloalkyl, C2-6alkenyl, C1-3alkylenearyl, arylC1-3alkyl, C(═O)Ra, aryl, heteroaryl, C(═O)ORa, C(═O)N(Ra)2, C(═S)N(Ra)2, SO2Ra, SO2N(Ra)2, S(═O)Ra, S(═O)N(Ra)2, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C1-4alkylenearyl substituted with one or more of SO2N(Ra)2, N(Ra)2, C(═O)ORa, NRaSO2CF3, CN, NO2, C(═O) Ra, ORa, C1-4alkyleneN(Ra)2, and OC1-4alkyleneN(Ra)2, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O) Het, C1-4alkyleneC(═O)N(Ra)2, C1-4alkyleneORa, C1-4alkyleneNRaC(═O)Ra, C1-4alkyleneOC1-4alkyleneORa, C1-4alkyleneN(Ra)2, C1-4alkyleneC(═O)ORa, and C1-4alkyleneOC1-4alkyleneC(═O)ORa; Ra is selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C1-3alkyleneN(Rc)2, aryl, arylC1-3alkyl, C1-3alkylenearyl, heteroaryl, heteroarylC1-3alkyl, and C1-3alkyleneheteroaryl; or two Ra groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom; Rb is selected from the group consisting of hydrogen, C1-6alkyl, heteroC3alkyl, C1-3alkyleneheteroC1-3alkyl, arylheteroC1-3alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl; Rc is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, aryl, and heteroaryl; Het is a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C1-4alkyl or C(═O)ORa; and pharmaceutically acceptable salts and solvates, in an amount sufficient to inhibit phosphatidylinositol 3-kinase delta activity in said leukocytes.
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