Inhibitors of human phosphatidyl-inositol 3-kinase delta

A method of inhibiting kinase activity of a phosphatidylinositol 3-kinase delta polypeptide comprising a step of contacting the polypeptide with a compound having a structure

• wherein A is an optionally substituted monocyclic 5-membered heterocyclic ring system containing two or three nitrogen atoms or a bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the bicyclic 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, and 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)ORa, arylOC1-3alkyleneN(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, OC2-4alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2-4alkyleneORa, 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, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8heterocycloalkyl, NHC(═O)C1-3alkyleneHet, OC1-4alkyleneOC1-4alkyleneC(O)ORb, C(═O)C1-4alkyleneHet, and NRC(═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-mernbered ring, optionally containing at least one heteroatom;
• R3 is selected from the group consisting of optionally substituted hydrogen, C1-6alkyl, 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, C1-6alkyl, 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, heteroC1-3alkyl, C1-3alkyleneheteroC1-3alkyl, arylheteroC1-3alkyl, and aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
• Rc is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cycloalkyl, aryl, and heteroaryl;
• Het is a 5- or 6-menibered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
• selected from the group consisting of 1,3-dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidine, piperazine, pyrroline, 2H-pyran, 4H-pyran, morpholine, thiomorpholine, piperidine, 1,4-dithiane, and 2,4-dioxane, and optionally substituted with C1-4alkyl or C(═O)ORa;
• and pharmaceutically acceptable salts or solvates thereof.

A compound having a general structural formula

• wherein A is an optionally substituted monocyclic 5-membered heterocyclic ring system containing two or three nitrogen atoms or a bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the cyclic 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, and 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)ORa, arylOC1-3alkyleneN(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, OC2-4alkyleneN(Ra)2, OC1-4alkyleneCH(ORb)CH2N(Ra)2, OC1-4alkyleneHet, OC2-4alkyleneORa, 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, arylOC1-3alkyleneN(Ra)2, arylOC(═O)Rb, NHC(═O)C1-3alkyleneC3-8heterocycloalkyl, 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, C1-6alkyl, 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;
• Rd is selected from the group consisting of hydrogen, C1-6alkyl, 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, heteroC1-3alkyl, C1-3alkyleneheteroC1-3alkyl, arylheteroC1-3alkyl, and 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, selected from the group consisting of 1,3-dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidirie, piperazine, pyrroline, 2H-pyran, 4H-pyran, morpholine, thiomorpholine, piperidine, 1,4-dithiane, and 1,4-dioxane, and optionally substituted with C1-4alkyl or C(═O)ORa;
• and pharmaceutically acceptable salts or solvates thereof,
• with the provisos that if X—Y is CH2S, then R3 is different from
• and if X—Y is CH2S, then R3 is different from —CH2CH(OH)CH2OH substituted phenyl.