Claims for Patent: 8,492,389

Summary for Patent: 8,492,389

Title:	Inhibitors of human phosphatidylinositol 3-kinase delta
Abstract:	Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3Kδ) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3Kδ plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3Kδ, while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3Kδ activity, including compounds that selectively inhibit PI3Kδ activity. Methods of using PI3Kδ inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3Kδ inhibitory compounds to inhibit PI3Kδ-mediated processes in vitro and in vivo.
Inventor(s):	Chanchal Sadhu, Ken Dick, Jennifer Treiberg, C. Gregory Sowell, Edward A. Kesicki, Amy Oliver
Assignee:	Icos Corp
Application Number:	US12/575,367
Patent Claims:	1. A compound of formula I wherein A is optionally substituted purinyl; X is selected from the group consisting of CH(CH3), CH(CH2CH3), and C(CH3)2; Y is NH; R1 and R2, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, aryl, heteroaryl, halo, NO2, ORa, OCF3, N(Ra)2, CN, OC2-4alkyleneORa, OC(═O)Ra, C(═O)Ra, and C(═O)ORa; R3 is optionally substituted and selected from the group consisting of aryl and arylC1-3 alkyl; and Ra is selected from the group consisting of hydrogen, C1-6 alkyl and C1-3alkylenearyl, or two Ra groups are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom selected from N, O, or S; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R3 is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, wherein R3 is unsubstituted phenyl, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 2, wherein phenyl is substituted with one to three groups selected from the group consisting of halo, ORa, C1-6alkyl, aryl, heteroaryl, NO2, N(Ra)2, NRaSO2CF3, NRaC(═O)Ra, C(═O)ORa, N(Ra)C1-4alkylene(Ra)2, SO2N(Ra)2, CN, C(═O)Ra, C1-4alkyleN(Ra)2, OC1-4alkyleneC≡CRa, OC1-4alkyleneC(═O)N(Ra)2, OC1-4alkylenearyl, OC1-4alkyleneheteroaryl, OC1-4alkyleneHet, OC1-4alkyleneN(Ra)2, and N(Ra)C1-4alkyleneN(Ra)2; wherein 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, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2, wherein R3 is phenyl substituted with one to three substitutents selected from the group consisting of Cl, F, CH3, CH(CH3)2, OH, OCH3, O(CH2)3N(CH3)2, OCH2C≡CH, OCH2C(═O)NH2, C6H5, NO2, NH2, NHC(═O)CH3, CO2H, N(CH3)CH2CH2N(CH3)2, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, wherein R1 and R2, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, halo, NO2, ORa, OCF3, N(Ra)2, and CN; and Ra is selected from the group consisting of hydrogen and C1-6 alkyl, or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein R1 and R2, independently, are selected from the group consisting of hydrogen, OCH3, Cl, Br, F, CH3, CF3, NO2, OH and N(CH3)2, or a pharmaceutically acceptable salt thereof. 8. The compound of claim 1, wherein A is optionally substituted with one to two substitutents selected from the group consisting of N(Ra)2, halo, C1-3alkyl, S(C1-3alkyl), and ORa, or a pharmaceutically acceptable salt thereof. 9. The compound of claim 1, wherein A is optionally substituted with one to two substitutents selected from the group consisting of NH2, NH(CH3), N(CH3)2, NHCH2C6H5, NH(C2H5), Cl, F, CH3, SCH3, and OH, or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1 selected from the group consisting of 2-[1-(2-fluoro-9H-purin-6-ylamino)ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-3-o-tolyl-3H-quinazolin-4-one; 2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; 5-methyl-2-(1-(9H-purin-6-ylamino)propyl)-3-o-tolyl-3H-quinazolin-4-one; 2-(1-(2-fluoro-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and 2-[1-(2-amino-9H-purin-6-ylamino)propyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one; or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.