CIS-MORPHOLINONE AND OTHER COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER

摘要

The present invention provides MDM2 inhibitor compounds of Formula (I), or the pharmaceutically acceptable salts thereof, wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.;

主权项

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein,X is O or —S(═O)2—;R1 is hydrogen, C1-6alkyl, —(CReRe)n C6-8aryl, —(CReRe)n C3-8cycloalkyl, —(CReRe)n3-8membered heterocycloalkyl, —S(═O)2C3-8cycloalkyl, —C(═O)C3-8cycloalkyl, orwherein any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6alkyl, halo, —CN, —CF3, —SRe, —S(═O)2Re, —CHF2, —CH2F, —NReRe, —OCF3, —OCHF2, —OCH2F, or —ORe;Q is —(CReRe)n C6-8aryl, —(CReRe)n3-8membered heterocycloalkyl, —(CReRe)n5-8membered heteroaryl, —(CReRe)n C3-8 cycloalkyl, —CN, —(CReRe)—OH, —C(═O)OH, —NReRe, —(CReRe)nORe, —C(═O)N(Re)S(═O)2Re, —C(═O)NReRe, —C(═O)NRe(CReRe)nC(═O)ORe, —C(═O)NRe(CReRe)nC(═O)NReRe, —N(Re)(CReRe)nC(═O)ORe, —OC(═O)NReRe, —S(═O)2C3-8cycloalkyl, —C(═O)N(Re)(CReRe)nOH, —C(═O)N(Re)(CReRe)n3-8membered heterocycloalkyl, —N(Re)C(═O)(CReRe)nOH, —N(Re)S(═O)2Re, —N(Re)C(═O)(CReRe)n C(═O)ORe, —C(═O)3-8membered heterocycloalkyl, —S(═O)23-8membered heterocycloalkyl, —C(═O)N(Re)S(═O)2C3-8cycloalkyl, —O(CReRe)n C(═O)Re, —C(═O)N(Re)(CReRe)n5-8membered heteroaryl, —N(Re)C(═O)(CReRe)n5-8membered heteroaryl, —C(═O)3-8membered heterocycloalkyl(CReRe)n C(═O)ORe, or —C(═O)(CReRe)n C(═O)ORe, wherein any heteroaryl or heterocycloalkyl group has one or more heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6alkyl, halo, —CN, —SRe, —C(═O)ORe, —CF3, —S(═O)2Re, —CHF2, —CH2F, —NReRe, —OCF3, —OCHF2, —OCH2F, or —ORe;R2 is hydrogen, C1-6alkyl, —(CReRe)nC(═O)ORe, —(CReRe)nNReRe, —(CReRe)nC(═O)NReRe, —(CReRe)nOH, —(CReRe)n C(═O)H, —(CReRe)n C6-8aryl, —(CReRe)n3-8membered heterocycloalkyl, —(CReRe)n5-8membered heteroaryl, —(CReRe)n CN, —(CReRe)nC(═O)5-8membered heterocycloalkyl, —(CReRe)nC(═O)N(Re)(CReRe)n3-8membered heterocycloalkyl, —(CReRe)n—CH(OH)CH2OH, —CH═CH5-8membered heteroaryl, —(CReRe)n CH═CReRe, —(CReRe)nOS(═O)2C1-6 alkyl, —(CReRe)nOS(═O)ORe, or —(CReRe)nOC(═O)NReRe, wherein any heteroaryl or heterocycloalkyl group has one or two heteroatoms independently selected from O, N or S, and wherein any cycloalkyl, heterocycloalkyl, heteroaryl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6alkyl, halo, —(CReRe)nhalo, —OC1-6alkyl, —OCF3, —OCF2H, —OCFH2, —CN, —S(═O)2CF3, —C(═O)NReRe, —C(═O)ORe, C6-8aryl, 5-8membered heteroaryl, —CF3, —SRe, —S(═O)2Re, —CHF2, —CH2F, —NReRe, or —ORe;R3 is hydrogen or C1-6alkyl;R4 is C6-8aryl or 5-9membered heteroaryl, wherein any heteroaryl group has one or more heteroatom independently selected from O, N or S, and wherein the aryl or heteroaryl group is substituted with from 1 to 3 substituents independently selected from C1-6alkyl, halo, —CF3, —CN, C3-8cycloalkyl, —SRe, —S(═O)2Re, —CHF2, —CH2F, —NReRe, —OCF3, —OCHF2, —OCH2F, or —ORe;R5 is C6-8aryl or 5-9membered heteroaryl, wherein any heteroaryl group has one or more heteroatom independently selected from O, N or S, and wherein the aryl or heteroaryl group is substituted with from 1 to 3 substituents independently selected from C1-6alkyl, halo, —CF3, —CN, C3-8cycloalkyl, —SRe, —S(═O)2Re, —CHF2, —CH2F, —NReRe, —OCF3, —OCHF2, —OCH2F, or —ORe;R6 is hydrogen or C1-6alkyl;R7 is hydrogen or C1-6alkyl;each Ra is independently hydrogen, C1-6alkyl, C2-6alkenyl, —(CReRe)nC3-8cycloalkyl, or —(CReRe)n C6-8aryl, wherein any cycloalkyl or aryl group can be unsubstituted or substituted with from 1 to 3 substituents independently selected from C1-6alkyl, halo, —CN, —SRe, —C(═O)ORe—CF3, —S(═O)2Re, —CHF2, —CH2F, —NReRe, —OCF3, —OCHF2, —OCH2F, or —ORe;each Re is independently hydrogen, C1-6alkyl, or —OH;each Rf is independently hydrogen, C1-6alkyl, or —OH;each n is independently 0, 1, 2, 3 or 4; andeach m is independently 0, 1, 2, 3 or 4,provided that R2 and R3 are not both hydrogen.