Inhibitors of mTOR and Methods of Making and Using

A compound of Formula I:

• or a single stereoisomer or mixture of isomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, where
• Z is —C(O)—;
• R1 is phenyl optionally substituted with one, two, or three R20 groups independently selected from nitro;
• cyano;
• halo;
• alkyl;
• alkenyl;
• alkynyl;
• haloalkyl;
• —NR15R15a;
• —NR15C(O)R18;
• —NR15S(O)2R18;
• —NR15C(O)NR15aR15b;
• —OR9;
• —C(O)OR9;
• —C(O)R26;
• —C(O)NR16R16a;
• alkyl substituted with one or two —C(O)NR16R16a;
• S(O)2R17;
• heteroaryl optionally substituted with 1, 2, or 3 R27;
• and optionally substituted heterocycloalkyl;
• or
• R1 is heteroaryl or an N-oxide thereof, optionally substituted with one, two, or three R21 groups independently selected from oxo;
• cyano;
• alkyl;
• alkenyl;
• alkynyl;
• halo;
• haloalkyl;
• hydroxyalkyl;
• alkoxy;
• alkoxyalkyl;
• optionally substituted cycloalkyl;
• optionally substituted cycloalkylalkyl;
• optionally substituted heterocycloalkyl;
• optionally substituted heterocycloalkylalkyl;
• optionally substituted heteroaryl;
• optionally substituted heteroarylalkyl;
• alkyl substituted with phenylalkyloxy;
• —OR24;
• —SR25;
• —S(O)R25;
• —S(O)2R25;
• —S(O)2NR15R15b;
• —C(O)OR22;
• —C(O)NR23R23a;
• —C(O)R24a;
• —NR23R23a;
• alkyl substituted with one or two —NR23R23a;
• —NR23C(O)OR24b;
• —NR23C(O)R23a;
• alkyl substituted with one or two —NR23C(O)R24a;
• —NR23C(O)NR23aR24;
• —NR23C(═NH)NR23aR24;
• and —NR23S(O)2R23a;
• R2 is phenyl or naphthyl, each of which is substituted with R3a, R3b, R3c, and R3d;
• R2 is HET1 optionally substituted with R4a, R4b, and R4c;
• or R2 is HET2 optionally substituted with R4a, R4b, R4c, and R4d;
• HET1 is a 5- or 6-membered heteroaryl where the ring atom to which Z is attached is a carbon atom;
• HET2 is an 8- to 14-membered fused bicyclic ring containing one, two, three, or four ring heteroatoms independently selected from O, S, S(O), S(O)2, and N, with the remaining ring atoms being carbon, where the ring atom attached to Z is carbon and where the ring attached to Z is aromatic and the other ring of HET2 is partially or fully unsaturated;
• R3a, R3b, R3c, and R3d are independently hydrogen;
• nitro;
• cyano;
• halo;
• alkyl;
• alkenyl;
• alkynyl;
• cyanoalkyl;
• haloalkyl;
• hydroxyalkyl;
• alkoxyalkyl;
• haloalkyl substituted with 1, 2, or 3 hydroxy;
• alkylsulfonylalkyl;
• —C(O)R28;
• —C(O)NR13R13a;
• —C(O)C(O)NR29R29a;
• —SR14;
• —S(O)R19;
• —S(O)2R6;
• —S(O)2NR7R7a;
• —OR9;
• —NR11R11a;
• alkyl substituted with one or two —NR8R8a;
• optionally substituted phenyl;
• optionally substituted phenylalkyl;
• optionally substituted heteroaryl;
• optionally substituted heteroarylalkyl;
• optionally substituted heterocycloalkyl;
• optionally substituted cycloalkyl;
• or optionally substituted cycloalkylalkyl;
• R4a, R4b, R4c, and R4d are independently nitro;
• cyano;
• halo;
• oxo, alkyl;
• alkenyl;
• alkynyl;
• cyanoalkyl;
• haloalkyl;
• hydroxyalkyl;
• alkoxyalkyl;
• haloalkyl substituted with 1, 2, or 3 hydroxy;
• alkylsulfonylalkyl;
• —C(O)R12;
• —C(O)NR13R13a;
• alkyl substituted with one or two groups independently selected from aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl;
• —C(O)C(O)NR29R29a;
• —SR14;
• —S(O)R19;
• —S(O)2R6;
• —S(O)2NR7R7a;
• —OR9;
• —NR11R11a;
• alkyl substituted with one or two —NR8R8a;
• optionally substituted phenyl;
• optionally substituted phenylalkyl;
• optionally substituted heteroaryl;
• optionally substituted heteroarylalkyl;
• optionally substituted heterocycloalkyl;
• optionally substituted heterocycloalkylalkyl;
• optionally substituted cycloalkyl;
• or optionally substituted cycloalkylalkyl;
• R5a and R5c are independently hydrogen, deuterium, or alkyl;
• R5h is hydrogen or halo;
• R5b is hydrogen, amino, or halo;
• R5d, R5e, R5f, and R5g are independently hydrogen or deuterium;
• R6 is halo;
• alkyl;
• alkenyl;
• alkynyl;
• haloalkyl;
• hydroxyalkyl;
• alkyl substituted with one or two —NR10R10a;
• alkyl substituted with one heterocycloalkyloxy;
• optionally substituted phenyl;
• optionally substituted phenylalkyl;
• optionally substituted heterocycloalkyl;
• optionally substituted heterocycloalkylalkyl;
• optionally substituted cycloalkyl;
• or optionally substituted cycloalkylalkyl;
• R7, R8, R10, R11, R13, R15, R15b, R16, R29, and R29a are independently hydrogen, alkyl, alkenyl, or alkynyl;
• R7a is hydrogen, alkoxy, alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkylsulfonylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl;
• R8a and R10a are independently hydrogen, alkyl, or alkoxycarbonyl;
• R9 is hydrogen;
• alkyl;
• haloalkyl;
• hydroxyalkyl;
• optionally substituted phenyl;
• or alkyl substituted with one or two —NR10R10a;
• R11a is hydrogen, alkyl, alkenyl, alkynyl, alkoxycarbonyl, alkylsulfonyl, or optionally substituted phenylsulfonyl;
• R12 is alkyl, alkoxy, or hydroxy;
• R13a is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl;
• R14 and R19 are independently alkyl;
• haloalkyl;
• or optionally substituted phenyl;
• R15a is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
• R16a is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, optionally substituted heterocycloalkyl, or optionally substituted heterocycloalkylalkyl;
• R17 is alkyl, alkenyl, alkynyl, amino, alkylamino, or dialkylamino;
• R18 is alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
• R22 and R23 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, or haloalkyl;
• R23a is hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
• R24 is hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, hydroxyalkyl, or optionally substituted phenylalkyl;
• R24a is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or optionally substituted heterocycloalkyl;
• R24b is alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
• R25 is alkyl or haloalkyl;
• R26 is alkyl;
• or optionally substituted heterocycloalkyl;
• each R27, when R27 is present, is independently selected from amino, alkylamino, dialkylamino, acylamino, halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or optionally substituted phenyl;
• and
• R28 is alkyl;
• haloalkyl;
• alkoxy;
• hydroxy;
• optionally substituted heterocycloalkyl;
• or optionally substituted phenyl.