US 2014/0235629 A1 · HETEROCYCLIC COMPOUNDS AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER

Abstract

The present invention provides MDM2 inhibitor compounds of Formula I or II, 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.

A compound of Formula I or II, or a pharmaceutically acceptable salt thereof,

wherein:
Q is O, S, —S(═O)—, —S(═O)2—, or —NRe;
Z is —C(═O)— or —S(═O)2—;
R1 is a 5 to 10 membered aryl or heteroaryl group, which heteroaryl group can contain from one to three heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —OH, —NO2, —NHC(═O)C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, —(CH2)nC(═O)Rf, —(CH2)nC(═O)NRfRf, —CN, —NRgRg or A,
or R1 and R5 together with the carbon atom to which they are attached can form a 3 to 6 membered cycloalkyl or heterocycloalkyl group, optionally containing a —(C═O)— group, which heterocycloalkyl group can contain from one to two heteroatoms independently selected from O, N or S, and the cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, —(CH2)nC(═O)Rf, —(CH2)nC(═O)NRfRf or —CN, and substituents on two adjacent carbons atoms of the cycloalkyl or heterocycloalkyl group can join together to form a five or six membered ring, including the two carbon atoms, fused to the cycloalkyl or heterocycloalkyl group,
or when R1 is substituted with —NRgRg, then Rg and Rg together with the nitrogen atom to which they are attached can form a 3 to 6 membered heterocycloalkyl group, which heterocycloalkyl group can contain from one to two additional heteroatoms independently selected from O, N or S, and the heterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F or —CN;
each A is independently a 5 or 6 membered aryl or heteroaryl group, which heteroaryl group can contain from one to three heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
R2 is a 5 to 10 membered aryl or heteroaryl group, which heteroaryl group can contain from one to three heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —OH, —NO2, —NHC(═O)C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3—OCF3, —OCHF2, —OCH2F, —(CH2)nC(═O)Rf, —(CH2)nC(═O)NRfRf, —CN, —NRgRg or B,
or when R2 is substituted with —NRgRg, then Rg and Rg together with the nitrogen atom to which they are attached can form a 3 to 6 membered heterocycloalkyl group, which heterocycloalkyl group can contain from one to two additional heteroatoms independently selected from O, N or S, and the heterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
each B is independently a 5 or 6 membered aryl or heteroaryl group, which heteroaryl group can contain from one to three heteroatoms independently selected from O, N or S, and the aryl or heteroaryl groups group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
R2a is hydrogen or —C1-3alkyl;
R3 is hydrogen, —C1-6alkyl, —C(═O)ORf, —C(═O)C1-6alkyl, —S(═O)2Rf, —S(═O)Rf, —ORf, —C(═O)NRfN(Rf)2, —C(═O)NRfS(═O)2Rf, —S(═O)2NRfC(═O)Rf, —S(═O)2NRfRf, —N(Rf)C(═O)NRfRf, —NRfC(═O)2Rf, —C(═O)NRfRf, —NRfS(═O)2Rf, —CN, —NRfRf, —C(═O)NOH, —NRfC(═O)ORf, —NRfC(═O)Rf, —C1-6alkyl substituted with from 1 to 3 hydroyl groups, —C1-6alkenyl, or a 5 or 6 membered aryl or heteroaryl group, which heteroaryl group can contain from one to four heteroatoms independently selected from O, N or S, and the aryl or heteroaryl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN, and any C1-6alkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —OH, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
R4 is hydrogen, —C1-6alkyl, —C2-6alkenyl, —CF3, —CH2F, —CHF2, —S(═O)2Rf, —SRf, —S(═O)Rf, —S(═O)2NRfRf, —NRfS(═O)2NRfRf, —C(═O)NRfRf, —NRfS(═O)2Rf, —C(═O)2Rf, —ORf, a 3 to 7 membered cycloalkyl or heterocycloalkyl, optionally containing a —(C═O)— group, or a 5 to 6 membered aryl or heteroaryl group, which heterocycloalkyl or heteroaryl group can contain from one to three heteroatoms independently selected from O, N or S, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl-OH, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or CN, and the —C1-6alkyl or —C2-6alkenyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —NRfRf, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or CN;
R5 is hydrogen or —C1-6alkyl;
R6 is hydrogen, —C1-6alkyl, —(CH2)NRfRf, or —(CH2)nC(═O)NRfRf;
each Ra is independently hydrogen, halo or —C1-6alkyl, or two Ra groups that are attached to the same carbon atom can form an (═O) group or a 3 to 6 membered cycloalkyl or heterocycloalkyl group, or an Ra group and R6 along with the atoms to which they are attached can form a 3 to 6 membered cycloalkyl or heterocycloalkyl group, which heterocycloalkyl group can contain from one to two heteroatoms independently selected from O, N or S, and the cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
each Rc is independently hydrogen, —C1-6alkyl, —C1-6alkyl-CF3, —CF3, a 3 to 6 membered cycloalkyl or heterocycloalkyl group, which heterocycloalkyl group can contain from one to two heteroatoms independently selected from O, N or S, and the cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
or two Rc groups that are attached to the same or adjacent carbon atoms can together with the carbon atom or atoms to which they are attached form or a 3 to 6 membered cycloalkyl or heterocycloalkyl group, which heterocycloalkyl group can contain from one to two heteroatoms independently selected from O, N or S, and the cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
each Rd is independently hydrogen or —C1-6alkyl;
each Re is independently hydrogen or —C1-6alkyl;
each Rf is independently hydrogen, —CN, —C1-6alkyl, —C1-6alkyl-CN, —C1-6alkyl-CF3, hydroxyC1-6alkyl, —C1-6alkylNReRe, or a 5 to 6 membered aryl, —C1-6alkylaryl, heteroaryl, or —C1-6alkylheteroaryl, or a 3 to 9 membered cycloalkyl, —C1-6alkylcycloalkyl, heterocycloalkyl or —C1-6alkylheterocycloalkyl group, which heteroaryl, alkylheteroaryl, heterocycloalkyl, or alkylheterocycloalkyl group can contain from one to three heteroatoms independently selected from O, N or S, and the alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl. —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
or when Rf and Rf are part of an NRfRf or CRfRf moiety in a group, then Rf and Rf together with the nitrogen or carbon atom to which they are attached can form a 3 to 7 membered heterocycloalkyl or cycloalkyl group, which heterocycloalkyl group can contain from one to two additional heteroatoms independently selected from O, N or S, and the heterocycloalkyl or cycloalkyl group can be unsubstituted or substituted with from one to three substituents independently selected from halo, —C1-6alkyl, —S(═O)2C1-6alkyl, —S(═O)C1-6alkyl, —OC1-6alkyl, —CF3, —OCF3, —OCHF2, —OCH2F, or —CN;
each Rg is independently hydrogen, or —C1-6alkyl;
and
each n is independently 0, 1, 2, 3 or 4, provided that the compound is not 2-((2R,5R,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((1S,2S)-2-(isopropylsulfonyl)cyclopentyl)-3-oxomorpholin-2-yl)acetic acid;
2-((2S,5R,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((1S,2S)-2-(isopropylsulfonyl)cyclopentyl)-3-oxomorpholin-2-yl)acetic acid;
2-((2R,5R,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((1R,2R)-2-(isopropylsulfonyl)cyclopentyl)-3-oxomorpholin-2-yl)acetic acid;
or 2-((2S,5R,6R)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-4-((1R,2R)-2-(isopropylsulfonyl)cyclopentyl)-3-oxomorpholin-2-yl)acetic acid.

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Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer

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Heterocyclic compounds as mdm2 inhibitors for the treatment of cancer

Life of this patent

Abstract

Claims45