2,6,7,8 SUBSTITUTED PURINES AS HDM2 INHIBITORS

摘要

The present invention provides 2,6,7,8 Substituted Purines as described herein or a pharmaceutically acceptable salt thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.

主权项

1. A compound represented by Formula I:Wherein
R1 is selected from the group consisting of C1-C6alkyl, —(CRa2)nCOOR11, —(CRa2)nNR5SO2R6, —(CRa2)nSO2NR5R6, —(CRa2)nC(O)NRcSO2N(Rc)2, —(CRa2)nC(O)R5, —(CRa2)nCONR5R6, —(CRa2)nCONR5SO2R6, —(CRa2)nCONR5OR6, —(CRa2)nOR5, —(CRa2)nS(O)Rc, —(CRa2)nS(O)2Rc, and nitrogen containing 5 or 6-membered heteroaryl, heterocyclic and heterocyclenyl ring, wherein the alkyl and 5 or 6-membered ring can be optionally substituted with ORc, SRc, NH2, nitro, CN, amide, COOR11, C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkyloxy, C1-C6hydroxyalkyl, C2-C6alkenyl, C1-C6alkyl-C(═O)O—, C1-C6alkyl-C(═O)—, C2-C6alkynyl, halo group, hydroxyalkoxy, —SO2NRcRc, —NRcSO2Rc, C1-C6alkylsulfonyl, C1-C6alkylamino or di(C1-C6)alkylamino; R2 is selected from the group consisting of aryl, heteroaryl, C3-C8cycloalkyl, —W—(CRaR9)tR7, and heterocyclic, wherein W is NRc or O, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic is optionally substituted with R12 selected from the group consisting of halo, CN, haloC1-C6alkyl, C1-C6alkyl, —(CRa2)zOR8, —(CRa2)zNHcRc, —(CRa2)zC(O)NRcRc, —(CRa2)zCOOR10, —(CRa2)zS(O)2Rc, —(CRa2)zaryl, —(CRa2)zheteroaryl, —(CRa2)zheterocyclic, —(CRa2)zC3-C8cycloalkyl, —(CRa2)zcyclenyl, and —(CRa2)zheterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl and heterocyclenyl of R12 can be optionally substituted with OH, NH2, nitro, CN, CON(Rc)2, —(CRa2)zCOOR10, C1-C6alkoxy, C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkyloxy, C1-C6hydroxyalkyl, C2-C6alkenyl, C1-C6alkyl-C(═O)O—, C1-C6alkyl-C(═O)—, C2-C6alkynyl, halo group, hydroxyalkoxy, —SO2NRcRc, —NRcSO2Rc, C1-C6alkylsulfonyl, C1-C6alkylamino or di(C1-C6)alkylamino; R3 is selected from the group consisting of —(CRa2)qNRcR8, —(CRa2)qOR8, —(CRa2)qSR8, —(CRa2)qC(O)R8, —(CRa2)qS(O)R8, —(CRa2)qS(O)2R8, —(CRa2)qCONRcR8, —(CRa2)qNRcC(O)R8, -T-C1-C6alkyl, C2-C6alkenyl, -T-aryl, -T-heteroaryl, -T-heterocyclic, -T-C3-C8cycloalkyl, -T-cyclenyl, and -T-heterocyclenyl, wherein the alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl and heterocyclenyl can be optionally substituted with halo, SRc, ORc, haloC1-C6alkyl, haloC1-C6alkoxy, —(CRa2)zCN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, —(CRa2)zC(O)OR10, —(CRa2)zC(O)R8, —(CRa2)zOR8, —(CRa2)zNRcR8, —(CRa2)zS(O)2R8, —(CRa2)zC(O)NRcR8, —(CRa2)zaryl, —(CRa2)zheteroaryl, —(CRa2)z C3-C8cycloalkyl, —(CRa2)zheterocyclic, —(CRa2)zheterocyclenyl, —(CRa2)zcyclenyl, —(CRa2)zSO2NRcRc, or —(CRa2)zO(CRa2)zD(CRa2)vQ, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic, heterocyclenyl and cyclenyl can further be optionally substituted with SH, OH, NH2, nitro, CN, CON(Rc)2, COOR10, C1-C6alkoxy, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6haloalkyloxy, C1-C6hydroxyalkyl, C1-C6alkyl-C(═O)O—, C1-C6alkyl-C(═O)—, C2-C6alkynyl, halo group, hydroxyalkoxy, —SO2NRcRc, —NRcSO2Rc, C1-C6alkylsulfonyl, C1-C6alkylamino or di(C1-C6)alkylamino; R4 is selected from the group consisting of C1-C6alkyl, —(CRa2)maryl, —(CRa2)mheteroaryl, —(CRa2)mheterocyclic, —(CRa2)mC3-C8cycloalkyl, —(CRa2)mcyclenyl, and —(CRa2)mheterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl, and heterocyclenyl can be optionally substituted with OH, SH, NH2, nitro, CN, CON(Rc)2, COOR10, C1-C6alkoxy, C1-C6alkyl, C3-C6cycloalkyl, haloC2-C6alkenyl, C2-C6alkenyl, C2-C6alkenoxy, C1-C6haloalkyl, C1-C6haloalkyloxy, C1-C6hydroxyalkyl, C1-C6alkyl-C(═O)O—, C1-C6alkyl-C(═O)—, C2-C6alkynyl, halo group, hydroxyalkoxy, —SO2NRcRc, —NRcSO2Rc, C1-C6alkylsulfonyl, C1-C6alkylamino or di(C1-C6)alkylamino; R5 is independently selected from the group consisting of H, C1-C6alkyl, —C0-C6alkyl-C3-C8cycloalkyl, —C0-C6alkyl-heteroaryl, —C0-C6alkyl-aryl, and —C0-C6alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, aryl, and heterocyclic can be optionally substituted with C2-C3alkenyl, C3-C6cycloalkyl, C1-C3alkoxy, OH, halo, NH2, C1-C3alkylamino, C1-C3dialkylamino or COOR11; R6 is independently selected from the group consisting of H, C1-C6alkyl, —C0-C6alkyl-C3-C8cycloalkyl, —C0-C6alkyl-heteroaryl, —C0-C6alkyl-aryl, and —C0-C6alkylheterocyclic, wherein the alkyl, cycloalkyl, heteroaryl, aryl, and heterocyclic can be optionally substituted with C2-C3alkenyl, C3-C6cycloalkyl, C1-C3alkoxy, OH, halo, NH2, C1-C3alkylamino, C1-C3dialkylamino or COOR11; R7 is selected from the group consisting of H, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, aryl, heteroaryl, and heterocyclic, wherein the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic can be optionally substituted with halo, nitro, CN, C1-C6haloalkyl, C1-C6haloalkyloxy, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, —C0-C6alkyl-C3-C8cycloalkyl, —C0-C6alkyl-heteroaryl, —C0-C6alkyl-aryl, —C0-C6alkylheterocyclic, —C0-C6alkylheterocyclenyl, —C0-C6alkylcyclenyl, —(CRa2)zNR5R6, —(CRa2)zNR5SO2R6, —(CRa2)zSO2NR5R6, —(CRa2)zC(O)R5, —(CRa2)zC(O)OR10, —(CRa2)zCONR5R6, —(CRa2)zCONR5OR6, —(CRa2)zNR5C(O)OR6, (CRa2)zNR5C(O)R6, —(CRa2)zOR5, —(CRa2)zS(O)Rc, and —(CRa2)zS(O)2Rc; R8 is independently selected from the group consisting of H, —(CRa2)s-heteroaryl, —(CRa2)s-aryl, —(CRa2)s-heterocyclic, —(CRa2)s-heterocyclenyl, —(CRa2)s-cyclenyl, —(CRa2)sC3-C8cycloalkyl, and C1-C6alkyl, wherein the heteroaryl, aryl, heterocyclic, heterocyclenyl, cyclenyl, cycloalkyl, and alkyl can be optionally substituted with OH, —N(Rc)2, NH2, nitro, CN, CON(Rc)2, COOR10, C1-C6alkoxy, C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6haloalkyl, C1-C6haloalkyloxy, C1-C6hydroxyalkyl, C1-C6alkyl-C(═O)O—, C1-C6alkyl-C(═O)—, C2-C6alkynyl, halo group, hydroxyalkoxy, —SO2NRcRc, —NRcSO2Rc, C1-C6alkylsulfonyl, C1-C6alkylamino, di(C1-C6)alkylamino, heteroaryl, aryl, heterocyclic, heterocyclenyl, or cyclenyl; R9 is independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, aryl, heteroaryl, and heterocyclic, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic can be optionally substituted with —C0-C6alkylORc, C0-C6alkylN(Rc)2, COOR10, nitro, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkyloxy, C1-C6hydroxyalkyl, C2-C6alkenyl, C1-C6alkyl-C(═O)O—, C1-C6alkyl-C(═O)—, C2-C6alkynyl, halo group, hydroxyalkoxy, —SO2NRcRc, —NRcSO2Rc, C1-C6alkylsulfonyl, heterocylic, or C(O)NHRc; R10 is independently selected from the group consisting of C1-C6alkyl, —(CRc2)zC3-C8cycloalkyl, —(CRc2)z-heteroaryl, —(CRc2)z-aryl, and —(CRc2)z-heterocyclic, wherein the heteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can be optionally substituted with C1-C6alkyl, OH, halo, or haloC1-C6alkyl; R11 is independently selected from the group consisting of H, C1-C6alkyl, —(CRc2)zC3-C8cycloalkyl, —(CRc2)zheteroaryl, —(CR2)zaryl, and —(CRc2)zheterocyclic wherein the heteroaryl, aryl, heterocyclic, cycloalkyl and alkyl can be optionally substituted with C1-C6alkyl, OH, halo, or haloC1-C6alkyl; Ra is independently H, ORc, NH2, halo, C1-C3alkyl, or C2-C4alkenyl, said alkyl or alkenyl is optionally substituted with OH, C1-C4alkoxy, NH2, halo, haloC1-C4alkyl, C3-C6cycloalkyl, or C2-C4alkenyl; Rc is independently H or C1-C3alkyl optionally substituted with C2-C3alkenyl, C3-C6cycloalkyl, C1-C3alkoxy, OH, halo, NH2, C1-C3alkylamino, or C1-C3dialkylamino; T is independently C2-C3alkenyl, —(CRa2)q—, —C(═CH2)—, —(CRa2)q—C(═CH2)—, —C(═CH2)—(CRa2)q—, —C(═NH)—, —(CRa2)q—C(═NH)—, or —C(═NH)—(CRa2)q—; D is a bond, —C(O)NRc—, —NRcC(O)—, or —NRc—; Q is H, COOR10, OH, heteroaryl or heterocyclic; n is independently 0, 1, 2 or 3; m is independently 0, 1 or 2; q is independently 0, 1, 2, or 3; s is independently 0, 1 or 2; t is independently 0, 1, or 2; v is independently 1, 2, 3 or 4; z is independently 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.