Details for Patent: 8,492,389
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Title: | Inhibitors of human phosphatidylinositol 3-kinase delta |
Abstract: | Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3K.delta.) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3K.delta. plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3K.delta., while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3K.delta. activity, including compounds that selectively inhibit PI3K.delta. activity. Methods of using PI3K.delta. inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3K.delta. inhibitory compounds to inhibit PI3K.delta.-mediated processes in vitro and in vivo. |
Inventor(s): | Sadhu; Chanchal (Bothell, WA), Dick; Ken (Bothell, WA), Treiberg; Jennifer (Redmond, WA), Sowell; C. Gregory (Mukilteo, WA), Kesicki; Edward A. (Bothell, WA), Oliver; Amy (Bothell, WA) |
Assignee: | ICOS Corporation (Indianapolis, IN) |
Filing Date: | Oct 07, 2009 |
Application Number: | 12/575,367 |
Claims: | 1. A compound of formula I ##STR00093## wherein A is optionally substituted purinyl; X is selected from the group consisting of CH(CH.sub.3), CH(CH.sub.2CH.sub.3), and C(CH.sub.3).sub.2; Y is NH; R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, C.sub.1-6 alkyl, aryl, heteroaryl, halo, NO.sub.2, OR.sup.a, OCF.sub.3, N(R.sup.a).sub.2, CN, OC.sub.2-4alkyleneOR.sup.a, OC(.dbd.O)R.sup.a, C(.dbd.O)R.sup.a, and C(.dbd.O)OR.sup.a; R.sup.3 is optionally substituted and selected from the group consisting of aryl and arylC.sub.1-3 alkyl; and R.sup.a is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and C.sub.1-3alkylenearyl, or two R.sup.a 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 R.sup.3 is optionally substituted phenyl, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, wherein R.sup.3 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, OR.sup.a, C.sub.1-6alkyl, aryl, heteroaryl, NO.sub.2, N(R.sup.a).sub.2, NR.sup.aSO.sub.2CF.sub.3, NR.sup.aC(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a, N(R.sup.a)C.sub.1-4alkylene(R.sup.a).sub.2, SO.sub.2N(R.sup.a).sub.2, CN, C(.dbd.O)R.sup.a, C.sub.1-4alkyleN(R.sup.a).sub.2, OC.sub.1-4alkyleneC.ident.CR.sup.a, OC.sub.1-4alkyleneC(.dbd.O)N(R.sup.a).sub.2, OC.sub.1-4alkylenearyl, OC.sub.1-4alkyleneheteroaryl, OC.sub.1-4alkyleneHet, OC.sub.1-4alkyleneN(R.sup.a).sub.2, and N(R.sup.a)C.sub.1-4alkyleneN(R.sup.a).sub.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 C.sub.1-4alkyl or C(.dbd.O)OR.sup.a, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2, wherein R.sup.3 is phenyl substituted with one to three substitutents selected from the group consisting of Cl, F, CH.sub.3, CH(CH.sub.3).sub.2, OH, OCH.sub.3, O(CH.sub.2).sub.3N(CH.sub.3).sub.2, OCH.sub.2C.ident.CH, OCH.sub.2C(.dbd.O)NH.sub.2, C.sub.6H.sub.5, NO.sub.2, NH.sub.2, NHC(.dbd.O)CH.sub.3, CO.sub.2H, N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, C.sub.1-6 alkyl, halo, NO.sub.2, OR.sup.a, OCF.sub.3, N(R.sup.a).sub.2, and CN; and R.sup.a is selected from the group consisting of hydrogen and C.sub.1-6 alkyl, or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein R.sup.1 and R.sup.2, independently, are selected from the group consisting of hydrogen, OCH.sub.3, Cl, Br, F, CH.sub.3, CF.sub.3, NO.sub.2, OH and N(CH.sub.3).sub.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(R.sup.a).sub.2, halo, C.sub.1-3alkyl, S(C.sub.1-3alkyl), and OR.sup.a, 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 NH.sub.2, NH(CH.sub.3), N(CH.sub.3).sub.2, NHCH.sub.2C.sub.6H.sub.5, NH(C.sub.2H.sub.5), Cl, F, CH.sub.3, SCH.sub.3, 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-quinaz- olin-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-quinazoli- n-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. |